Autonomic Nervous System - Apex Flashcards by Abbie Barkley

Examples of positive feedback control in the human body include: (Select 3).:
a. generation of an AP
b. PaCO2 regulation
c. coagulation cascade
d. core temperature
e. serum glucose concentration
f. childbirth

A, F, and C

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Homeostasis is a steady-state condition that comes with a price - it requires ____ to maintain the system.

energy

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What does a negative feedback system dO?

Reverse a disturbance in some factors and leads to stability

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What does a positive feedback system do?

Enhances or accelerates a disturbance in some factors and usually leads to instability

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Any physiologic system that needs to be maintained in a normal range (set point) requires a ____.

control system

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What four things must a control system be able to do:

sense the regulated variable
compare the input signal with an internal reference/set point
Multiply the error signal by a proportionality coefficient (the gain) to produce an output signal
adjust the important factor by activating an effector system

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What is the most common control system for maintaining homeostasis?

A closed negative feedback loop

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What are the sensors for the regulated variable - PaCO2?

central chemoreceptors

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CO2 is hydrated in the ____, forming ____ which spontaneously dissociates into ___ and ___.

CSF; H2CO3; H+ and HCO3-

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The PaCO2 is directly reflected by the ____, which is detected by central chemoreceptors in the _____ of the _____.

H+; retrotrapezoid nucleus of the medulla

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What is the feedback controller for PaCO2?

Dorsal respiratory group (DRG)/central pattern generator (CPG)

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What are the effectors for the regulated variable - PaCO2?

muscles of inspiration

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An increased PaCO2 (the disturbance) results in a decreased PaCO2. What type of system is this?

A negative feedback control system

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What is the sensor for the regulated variable - cervical opening?

Stretch receptors in the cervix

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During L&D, sensory impulses from the stretch receptors in the cervix are sent to the _____.

hypothalamus

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What is the feedback controller for the regulated variable - cervical opening?

The periventricular and supraoptic nuclei of the hypothalamus

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Increased stretch impulses from the cervix received at the hypothalamus stimulate the _______ to release more _____.

posterior pituitary (neurohypophysis); oxytocin

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What are the effectors for the regulated variable - cervical opening?

Oxytocin and the myometrium

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Oxytocin binds to G protein-coupled receptors (Gq) on the _____, producing more ______.

myometrium; powerful uterine contractions

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The fetus pushing more forcefully against the cervix and stimulating more oxytocin release is an example of which type of system?

Positive feedback cycle system

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Oxytocin also stimulates _____ production by the uterine lining.

prostaglandin

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Negative feedback or positive feedback??

Control of serum sodium concentration

Negative feedback

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Negative feedback or positive feedback??

Enhances or accelerates a disturbance in a vital parameter

Positive feedback

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Negative feedback or positive feedback??

Propagation of an AP

Positive feedback

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Negative feedback or positive feedback?? Leads to stability in a vital parameter

Negative feedback

Negative feedback or positive feedback?? Leads to instability in a vital parameter

Positive feedback

Negative feedback or positive feedback?? Opposes or reverses a disturbance in a vital parameter

Negative feedback

Which method of cell signaling occurs when a cell responds to a chemical signaling molecule that the cell itself produced and secreted? a. endocrine signaling b. paracrine signaling c. neurotransmitter signaling d. autocrine signaling

D - autocrine signaling

What is the intracellular response to extracellular signals called?

Cell signaling/signal transduction

The conversion of info into a chemical change is called _____, a universal property of living cells.

signal transduction

Info arrives at cells in what 4 forms:

1. Purely physical (energy) 2. Chemical 3. Cellular 4. Extracellular matrix molecules

What are examples of purely physical/energy forms?

light, sound, heat, pressure, electricity

What are examples of chemicals?

NT, hormones, eicosanoids, drugs, toxins

What are examples of a cellular form of information arriving at cells?

Gap junctions

What are extracellular matrix molecule examples?

Collagen (think of PLT adhesion), integrins, laminin

What are the 3 main methods of intracellular communication?

1. endocrine 2. paracrine 3. autocrine

Endocrine cell signaling = _________

a signaling molecule (i.e., a hormone) is secreted by an endocrine cell and transported through the circulation where it acts on a distant target cell

What is neuroendocrine signaling?

A specific type of endocrine signaling, where a neuron is the source of the hormone secreted into the blood

What is an example of neuroendocrine signaling?

The adrenal medulla releases epinephrine that binds to B1 receptors on the heart

What is paracrine signaling?

A chemical signaling molecule is released by one cell and acts locally to regulate the behavior of a neighboring cell

_____ cell signaling is a specific form of paracrine signaling.

Neurotransmitter

What is autocrine signaling?

A cell responds to a signaling molecule that it also produced.

NE binding to a presynaptic A2 receptor on the same nerve terminal that released NE is an example of what type of signaling?

Autocrine

What does autocoids mean?

Local hormone

Where are autocoids and paracrine hormones produced?

Locally

Autocoids and paracrine hormones are released in smaller or larger quantities than endocrine hormones?

Smaller

T/F: Autocoids and paracrine hormones are intended to act locally and are metabolized locally.

True

A chemical molecule that binds to a receptor and initiates a cellular response is called a: a. second messenger b. transducer c. ligand d. kinase

C - ligand

What does signal transduction exhibit?

specificity and sensitivity amplification integration feedback compartmentalization desensitization

The flow of info in a signal transduction sequence follows _____ pathways.

Orderly

What are the 6 processes in signal transduction sequences?

1. recognition 2. transduction 3. transmission 4. modulation 5. response 6. termination

What are the 4 types of receptor-based signal transducers?

1. transmembrane G protein-coupled receptors (GPCR) 2. Transmembrane gated ion channels 3. transmembrane enzyme-linked receptors 4. Soluble nuclear (intracellular) receptors

______ is imparted by the cell-specific receptor and is mediated by the same kinds of weak, non-covalent forces the mediate enzyme-substrate interactions.

Specificity (selectivity)

Bonds ordered from weakest to strongest: ____ < _____ < ____ < ____ < _____

Van der Waals < hydrophobic < Hydrogen < ionic < covalent

When does amplification by enzyme cascade result?

When an enzyme associated with a signal receptor is activated, and in turn catalyzes the activation of many molecules of a second enzyme, which activates a third enzyme, and so on

What is integration?

The ability of a signal-transducing system to receive multiple signals and produce a unified response appropriate to the cell's needs

Multiple components of signaling pathways are often brought together on _____ to increase their local concentration and effects.

Scaffold proteins

_____ are scaffolding proteins in addition to calcium channels.

Ryanodine receptors

When does desensitization occur?

When a signal is present continuously, desensitization of the receptor system results. (when the stimulus falls below a certain threshold, the system again becomes sensitive)

What is the general flow of info through G protein-coupled receptor signal transduction pathways?

1st messenger --> receptor --> effector --> 2nd messenger --> cellular response

The 1st step of signaling sequences is ____.

recognition of the signal by its receptor

All receptors are _____

proteins

A general term for any chemical that binds to a receptor is what?

Ligand (note - ligand immediately implies that there's a receptor involved)

A ligand is also called what?

the first messenger

What initiates the signaling sequence?

Energy from the stimulus-receptor interaction causes a conformational change in the receptor and then initiates the signaling sequence

What is the second stage of the signaling sequence?

TRANSDUCTION of the extracellular message into an intracellular signal or 2nd messenger

The conformational change of a receptor triggers either _____ or causes the receptor to _____.

catalytic activity intrinsic to the receptor; interact with membrane or cytoplasmic enzymes

The final consequence of RECOGNITION + TRANSDUCTION is the generation of a _____ or the activation of a _____.

second messenger; catalytic cascade

What messengers are extracellular signals?

1st

What messengers are intracellular signals?

2nd

_____ are extracellular signals, ____ are intracellular signals.

1st messengers; 2nd messengers

What occurs are tranduction?

TRANSMISSION

What is transmission during the signal sequence?

The second messenger's signal to the appropriate effector(s)

T/F: There are multiple pathways for signal transmission.

True

What are some key activities in signal transmission pathways?

1. activation of kinases that add phosphates to proteins 2. release or sequestration of intracellular ions 3. regulation of metabolic processes

____ and _____ typically occur during transmission

Amplification and integration

What stage of the signaling sequence does amplification typically occur?

Transmission

What stage of the signaling sequence does integration typically occur?

Transmission

What occurs after transmission?

MODULATION of downstream chemicals

What are two common modulation/"on/off" events?

enzymatic phosphorylation or dephosphorylation

What occurs after modulation?

RESPONSE of the cell to the initial stimulus

What are the different types of responses?

proliferation, differentiation, cell movement, metabolism, cell behavior

What occurs after the response stage of the signal sequence?

TERMINATION of the response

How is termination often accomplished?

feedback control

What is ATP?

adenosine triphosphate

What is IP3

Inositol triphosphate

Phenylephrine is a ____ for the ____ receptor.

ligand/agonist/first messenger; alpha-1

____ is a ligand for purinergic receptors.

ATP / adenosine

What is an example of a drug that has an extracellular target?

Dabigatran

What is an example of a drug that has an adhesion molecules?

Eptifibatide

ID the 4 categories of receptor-based signal transducers.

1. G protein coupled receptors 2. Gated ion channels 3. Enzyme-linked receptors 4. Soluble nuclear receptors

What is another name for a chemical that binds to a receptor?

ligand

What family of enzymes catalyzes the addition of a phosphate group to a molecule?

Kinases

What chemical messengers are derived from arachidonic acid? (select 3) a. prostaglandins b. thyroxine c. aldosterone d. leukotrienes e. dopamine f. anadamide

A - prostaglandins D - leukotrienes F - anandamide

Most chemical signals fall into 4 categories of molecules: 1. ______ 2. ______ 3. ______ 4. ______

1. small hydrophilic molecules 2. lipophilic molecules 3. peptides and proteins 4. others

Where are small hydrophilic molecules, peptides, and protein messengers stored?

In vesicles inside the cells that synthesize these molecules

______, _____, ____, and _____ are molecules that are not stored in vesicles.

Lipophilic molecules, purine, gas, and endocannabinoid messengers

Chemical messenger molecules bind to either _____ receptors or ____ receptors.

cell-surface or intracellular (cytoplasmic or nuclear)

What are the small hydrophilic chemical messenger classes?

Amino acids BIogenic amines choline esters iodothyronines

What are 4 examples of amino acids?

1. glycine 2. glutamate 3. GABA (y-aminobutyric acid) 4. aspartate

What are 5 examples of biogenic amines?

1. dopamine 2. norepineprhine 3. epinephrine 4. serotonin (5-HT) 5. histamine

What is an example of choline esters?

acetylcholine

What are 2 examples of idothyronines?

1. thyroxine (T4) 2. triiodothyronine (T3)

Small hydrophilic molecules are polar molecules are are ____ at physiologic pH.

ionized.

Do small hydrophilic chemical messengers readily cross plasma membranes?

No - therefore needs cell-surface receptors

____ of an amino acid precursor is a theme.

Decarboxylation

What 4 things are derived from tyrosine?

1. dopamine 2. NE 3. Epi 4. iodothyronines

T/F: GABA and glutamate can be intercoverted.

True

How are small hydrophilic chemical messengers typically released?

exocytosis (exception is T3&T4)

T3 and T4 are released through a ____

transporter

What are the 3 types of lipophilic chemical messengers?

1. steroids 2. eicosanoids 3. miscellaneous

Vitamin D3 and retinoids are _____ messengers.

Lipophilic (nonpolar)

Prostaglandins are _____

eicosanoids

Leukotrienes are _____

eicosanoids

Thromboxanes are _____

Eicosanoids

Steroids are derived from what?

cholesterol

How do steroids circulate in the blood?

bound to a protein

T/F: Steroids can diffuse through the lipid bilayer of plasma membranes.

True

Where do steroids to receptors of target cells?

in the cytoplasm or nucleus of target cells

What are eicosanoids derived from?

polyunsaturated fatty acids w/ 18, 20, and 22 carbons

_______ is the main precursor of eicosanoids.

Arachidonic acid (20 carbons)

Eicosanoids primarily have endocrine, autocrine, or paracrine actions?

autocrine and paracrine

T/F: Unlike steroids, eicosanoids usually bind to cell surface receptors.

True

What is calcitriol, 1,25-dihydroxycholecalciferol?

Vitamin D3

What is 1,25(OH)2D3?

Vitamin D3

______ is a cholesterol derivative but it does not retain the cholesterol ring structure.

Vitamin D3

Do steroids retain the cholesterol ring strucutre?

Yes

Retinoids are derived from what?

Vitamin A

Retinoids play a role in ______.

growth and development

Peptides and protein chemical messengers are generally ____ molecules.

hydrophilic (polar)

Peptides and protein chemical messengers do or do not readily cross plasma membranes?

Do not

How do peptides and protein chemical messengers circulate in the bloodstream?

As unbound molecules

____ and _____ are nucleotides and nucleosides.

ATP and Adenosine

Adeonsine and ATP are _____.

purines

T/F: Adenosine and ATP are stored in vesicles.

False

CO and NO are or are not lipid soluble?

Are

What kind of action do CO and NO have?

paracrine

What is NO synthesized from?

amino acid L-arginine

NO and CO serve as ____ neurotransmitters.

Retrograde

Anandamide (AEA) and 2-arachidonylgycerol (2-AG) are what type of chemical messengers?

Endocannabinoids

What are endocannabinoids derived from?

arachidonic acid

What receptors do endocannabinoids bind to?

CB-1 (CNS) and CB-2 (peripheral)

Endocannabinoids are lipophilic or hydrophilic?

Lipophilic

CB-1 and CB-2 are _____ receptors.

G protein-coupled

The brain has more _____ receptors than any other type of G protein-coupled recetpor!

cannabinoid

Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules??? Insulin - ___________

Peptide and protein molecules

Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules??? NO - ___________

Lipophilic

Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules??? Angiotensin II - ___________

Peptide and protein

Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules??? Thyroxine - ___________

Hydrophilic

Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules??? Calcitriol - ___________

Lipophilic

Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules??? Substance P - ___________

Peptide and protein

Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules??? GABA - ___________

Hydrophilic

Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules??? Aldosterone - ___________

Lipophilic

Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules??? Acetylcholine - ___________

Hydrophilic

Which categories of signaling molecules are stored in vesicles in the cell that synthesized the molecules?

1. small hydrophilic chemical messengers 2. peptide and protein chemical messengeres

Which lipophilic chemical messengers are not derived from cholesterol?

eicosanoids, retinoids, endocannabinoids

Dopamine, Epi, NE, and the idothyroinines are derived from which amino acid?

Tyrosine

How many times does a G protein-coupled receptor span the plasma membrane?

What is the largest and most diverse family of receptors on the cell surface?

G protein coupled receptors (GPCR)

What ligands bind to GPCRs?

NT, hormones, vasoactive peptides, odorants, tastants, and local chemical factors

About ___ to ___ of all drugs target GPCR.

1/2 to 2/3

G proteins are molecular switches and can _____ themselves through inherent GTPase activity in the ____ subunit.

inactivate; alpha

In the GPT-loaded state, the ____ interacts with downstream effects. What may also interact with downstream effectors?

alpha subunit; beta-gamma complex

What are the 4 G protein families?

1. Gs (stimulatory) 2. Gi (inhibitory) 3. Gq 4. G12,13

What does the following represent? Ligand --> GPCR --> Effector --> 2nd messenger --> Cell Resposne

The sequence of signal transduction through GPCR

What 3 essential components characterize signal transduction through GPCRs?

1. plasma membrane receptor with 7 transmembrane helical segments 2. A guanosine nucleotide-binding protein (g protein) activates the effector enzyme/path 3. An effector (usually enzyme) generates 2nd messenger

GPCRs have a plasma membrane receptor with _______ transmembrane ___ segments.

7; helical (7-TM seven-helix or serpentine receptor)

What do G proteins link?

receptor activation with a variety of downstream effects

The ___ class of G proteins are associated with 7-TM receptors.

Heterotrimeric (αβᵞ subunits)

When are G proteins turned ON?

when a ligand binds to the receptor binding site

When are G proteins turned OFF?

By the intrinsic GTPase activity in the alpha subunit

GDP is bound to the ____ subunit.

alpha

When activated, the 𝜶βᵞ complex of GPRC disassembles into a free GTP bound ___ subunit and a separate ___ complex.

𝜶; βᵞ

A _____ will stimulate (or inhibit) the production of a second messenger that will ultimately produce a change in cellular function.

G𝜶 subunit

Major effector targets of G𝜶 subunits include: (3)

1. adenylate cyclases (AC) 2. Phospholipase C (PLC) 3. Phospholipase A2 (PLA2)

T/F: The βᵞ complex can interact with down stream effectors.

True

What are major effector targets for Gβᵞ subunits? (3)

1. Gi, 0-regulated potassium channels (GIRK) 2. voltage-gated calcium channels 3. beta-adrenergic receptor kinase (BARK)

The alpha subunit has intrinsic GTPase activity, which catalyzes the hydrolysis of GTP to ___ and ___.

GDP and Pi

Gs stimulates _____

adenylyl cyclase

Gi inhibits ____

adenylyl cyclase

Cq11 stimulates _____

phospholipase C (PLC)

C12,13 activates ______

small G proteins

____ toxin chemically alters the Gs subunit to inhibit the intrinsic GTPase activity.

Cholera

Cholera inhibits the intrinsic GTPase activity. What occurs because of this?

continuous activation of the G protein and adenylate cylcase --> cell is swamped with cAMP --> stimulation of the export of fluid across the intestinal epithelium

____ toxin chemically alters the Gi,0 subunit

Pertussis

McCune-Albright syndrome is characterized by defects of ______.

hormonal regulation

What causes McCune-Albright syndrome?

A gain-of-function mutation of Gs that correlates w/ a massive disturbance of Gs controlled. hormone production

What causes pseudohypoparathyroidism?

A loss-of-function mutation of Gs (results in effects of PTH being suppressed --> premature puberty w/ obesity, growth retardation, and skeletal deformities)

G-alpha subunit target effector OR G-beta/gamma subunit target effector??? Adenylyl cyclase

alpha

G-alpha subunit target effector OR G-beta/gamma subunit target effector??? Phospholipase C

alpha

G-alpha subunit target effector OR G-beta/gamma subunit target effector??? Voltage-gated Ca channels

beta/gamma

G-alpha subunit target effector OR G-beta/gamma subunit target effector??? Gi,0-regulated potassium channels

beta/gamma

G-alpha subunit target effector OR G-beta/gamma subunit target effector??? Phospholipase A2

alpha

G-alpha subunit target effector OR G-beta/gamma subunit target effector??? Beta-adrenergic receptor kinase

beta/gamma

Which heterotrimeric G-protein subunit contains the intrinsic GTPase activity?

alpha

Match each enzyme with the substrate --> second messenger reaction the enzyme catalyzes. Phospholipase A2, Adenylyl Cyclase, and Phospholipase C ATP --> cAMP PIP2 --> IP3 + DAG Phospholipid --> arachidonic acid

Phospholipase A2 + Phospholipid --> arachidonic acid Adenylyl Cyclase + ATP --> cAMP Phospholiapse C + PIP2 --> IP3 + DAG

GPCRs target what # of downstream effectors that produce second messengers?

Adenylyl cyclase ---> ___________

cyclic adenosine monophostate (cAMP)

PHospholipase C (PLC) ---> _________

inositol triphosphate (IP3) & diacylglycerol (DAG)

Phospholipase A2 (PLA2) --> ________

Eicosanoids (20-carbon lipid mediators)

T/F: Second messenger effects are tissue specific.

True

Second messenger effects are ____ specific.

tissue

____ plays a key role int he regulation of intracellular signal transduction.

cAMP

The intracellular effects of cAMP are mediated by the enzyme _________, ____.

cAMP-dependent protein kinase, PKA

_____ is a second messenger that leads to Ca2+ release from intracellular storage sites.

IP3 (inositol-1,4,5,-triphosphate)

Many downstream signaling events mediated by Ca2+ are modulated by a Ca2+ sensing and binding protein, _____.

calmodulin (CaM)

What is the function of adenylyl cyclase?

To convert ATP to cyclic adenosine monophosphate (cAMP)

IP3 and DAG are ____ messengers

second

___ together with ___ activates PLC

Gq,11 & Ca2+

IP3 binds to what channels and where?

Ca2+ channels on the endoplasmic reticulum

What is released after IP3 binds to a channel?

Calcium

DAG in the membrane acts as a docking site for and activator of _____.

protein kinase C (PKC)

Phospholipase A2 is a ___ dependent enzyme.

Ca2+

Phospholipase A2 liberates what from the cell membrane?

Arachidonic acid

Arachidonic acid is the precursor to how many families of lipid signaling. molecules?

What 3 lipid signaling molecules is arachidonic acid the precursor to?

1. Prostaglandins and thromboxanes (porstanoids) 2. Leukotrienes 3. CYP450 monooxygenases

CYP450 monoxygenases catalyze the formation of ____ and ____ from the ____ substrace.

HETEs (hydroxyeicosatetraenoic acid); EET (cis-epoxyeicosatrienoic acid); arachidonic acid

Leukotrienes are generated when ___ encounters lipoxygenase.

arachidonic acid

Prostaglandins and thromboxanes are produced by the initial action of ____ on the arachidonic acid substrate.

cyxlooxygenases

Prostanoids, leukotrienes, HETEs, and EETs are collectively called _____.

Eicosanoids

In cardiac myocytes, increased cAMP does what?

enhances contractiliy

In cardiac myocytes, increased cAMP enhances contractility (____ receptors effects).

Beta-1

_____ messenger effects are tissue-specific.

Second

In smooth muscle of airways and vessels, increased cAMP causes _______.

relaxation and dilation.

In smooth muscle of airways and vessels, increased cAMP causes relaxation and dilation (_____ receptor effects).

Beta-2

In PLTs, increased cAMP _____.

reduces PLT aggregation

In principal cells of the nephron, increased cAMP ___________________.

promotes insertion of aquaporin-2 water channels in the apical membrane

Think of ____ as the sensors of second messengers.

protein kinases

What are kinases?

Enzymes that catalyze the addition of phosphate groups (PO4 -2) to their substrate

What are common tragets for kinases?

downstream proteins

_____ catalyze the removal of phosphate groups from their substrate.

Phophatases

cAMp activates ____ to modify cellular function.

protein kinase A (PKA)

Protein Kinase A (PKA) contains 2 _____ and 2 _____.

regulatory subunits; catalytic subunits

What happens when cAMP binds to the regulatory subunits of PKA?

It causes dissociation of the catalytic subunits

What are the catalytic subunits of PKA?

Serine/threonin (Ser/Thr) kinases

What terminates the action of cAMP?

Phosphodiesterases

What terminates the action of protein kinases?

Protein phosphatases

DAG is lipophilic or hydrophilic?

Lipophilic

DAG and Ca2+ activate what?

Protein Kinase C (PKC)

What cellular functions is PKC involved in? (its a lot....)

1. receptor desensitization 2. modulating membrane structure events 3. regulating transcription 4. mediating immune responses 5. regulating cell growth 6. learning and memory

When is the action of DAG terminated?

When the molecule is recycled into new phospholipids

IP3 is the ___ messenger that liberates ___ from intracellular storage sites.

second; Ca2+

Ca2+ is released from ER into the ____, resulting in a dramatic increase in intracellular or extracellular Calcium?

cytoplasm; intracellular

A high _____ activates several Ca2+ dependent protein kinases and phosphatases.

cytosolic [Ca2+]

Ca2+ signals are terminated by ATP-dependent processes: 1. ______________________ 2. _______________________

Ca2+ is returned into the ER Ca2+ is pumped out of the cell

When is the action of IP3 terminated?

when the molecule is recycled into new phophoslipids

Freely available intracellular Ca2+ is a ____ messenger.

2nd

_____ is directly or indirectly involved in most cell processes, from fertilization of the ovum to cell death.

Intracellular Ca2+

Unlike other second messengers, ____ is NOT synthesized, liberated from a precursor molecule, or activated by enzymes.

Calcium (it is the increased intracellular Ca2+ that is the signal)

What are the sources of Cytoplasmic Ca2+? (6)

1. voltage-gated Ca channels 2. storage- operated Ca channels 3. nonselective TRP ion channels 4. ionotropic NT receptors (NMDA) 5. IP3-controlled Ca channels (ER) 6. RyR Ca selective channels

Downstream Target of Ca2+: Voltage-gated calcium channels - _____

proteins that buffer calcium - calmodulin and calsequestrin

Downstream Target of Ca2+: storage-operated calcium channels - _____

Calcium sensor proteins (camodulin, troponin C, synaptotagmin [presynaptic vesicle exocytosis])

Downstream Target of Ca2+: Nonselective TRP ion channels - _____

enzymes (PLA2, PKC, NO synthases)

Downstream Target of Ca2+: Ionotropic NT receptors (NMDA) - _____

Receptors and ion channels: IP3 receptors, RyRs, Ca-activated K and Cl channels

Removal of cytoplasmic reticulum.... voltage-gated calcium channels = _________

Na+-Ca2+ Exchanger (NCX) at the plasma membrane

Removal of cytoplasmic reticulum.... storage-operated calcium channels = _________

Ca2+-ATPase ("pump") at the plasma membrane (PMCA)

Removal of cytoplasmic reticulum.... Nonselective TRP ion channels = _________

Ca2+-ATPase at the sarcoplasmic (muscle) or endoplasmic reticulum (SERCAs)

What Ca2+ sending and binding protein modulates may downstream events mediated by Ca2+?

Calmodulin (CaM)

When intracellular Ca2+ concentration increases, _____ Ca2+ binds to CaM inducing a major conformation change to the protein.

3-4

The active Ca2+/CaM complex has a wide range of downstream targets including: 1. 2. 3. 4.

1. NO synthase 2. Ca2+/CaM dependent protein kinases (ex: myosin light-chain kinase) 3. adenylyl cyclase 4. cAMP-specific PDE

caMP, DAG, IP3, or iCa??? Lipid second messenger

DAG

caMP, DAG, IP3, or iCa??? Generated from PIP2 and stays in the plasma membrane

DAG

caMP, DAG, IP3, or iCa??? Targets ligand activated Ca channels on the ER

IP3

caMP, DAG, IP3, or iCa??? IP3 releases it from the ER

iCa

caMP, DAG, IP3, or iCa??? Removed from the cytoplasm by pumps and transporters

iCa

caMP, DAG, IP3, or iCa??? Generated from PIP2 and diffuses in the cytoplasm

IP3

caMP, DAG, IP3, or iCa??? Activates PKA

cAMP

caMP, DAG, IP3, or iCa??? Adenylyl cyclase catalyzes production

cAMP

caMP, DAG, IP3, or iCa??? ATP is the precursor

cAMP

Which G protein alpha subunit activates adenylyl cyclase?

G-alpha S activates adenylyl cyclase

Which 2 Ca transporters are found in the plasma membrane

1. sodium-calcium exchanger (NCX) 2. Ca2+ ATPase (pump, PMCA)

What enzyme family catalyzes the addition of a phosphate group to a substrate?

Kinases catalyze the addition of a phosphate group to their substrates

What enzyme produces IP3 and DAG from PIP2?

PLC (phopholipase C)

The 2 types of synpases in the human body are (select 2): a. chemical b. thermal c. mechanical d. electrical

A and D

_____ play a crucial role in AP and other electrical behavior of membranes.

Ion channels

Ion channels usually have what type of pores?

gated

What helps the nervous system get the right signal to the right place in the body at the right time?

An intercellular junction called the synpase

What are the two types of synapses?

electrical and chemical

____ synapses are far more prevalent and diverse.

Chemical

____ receptors are the key proteins of signal transduction at chemical synapses.

NT receptors are transmembrane proteins that are either: 1. _____ 2. _____

1. ion channels (ionotropic receptors) 2. coupled to heterotrimeric G proteins (metabotropic receptors)

____ synapses are polarized. What does this mean?

Chemical; primarily one-way communication

What are chemical synapses comprised of?

A presynaptic terminal, synaptic cleft, and postsynaptic membrane

What is the presynaptic terminal also called?

axon terminal, synaptic bouton, or synaptic knobs

How wide is the synaptic cleft on chemical synapses?

20-40 nm wide

Ion channels are integral membrane proteins that form ________ pores through which selected ions can pass.

water-filled pores

T/F: Ion channels exhibit ion selectivity.

True

What type of channels usually have gated pores?

Ion channels

What are the 3 different types of gated ion channels?

1. voltage-gated (membrane) 2. ligand-gated (chemical) 3. Mechanically-gated (pressure/sensory receptors)

T/F: ALL ion channels are gated.

False - not all ion channels are gated

What is an example of an ion channel that is not gated?

"leaky" potassium channels that establish resting membrane potential

Chemical synapses convert a ____ signal ➡ a ____ signal through the release of NT.

electrical; chemical

Chemical synapses communicate messages in what direction?

one direction from the presynaptic membrane to the postsynaptic membrane, across the synaptic cleft

NT act as endocrine, paracrine, or autocrine messengers?

paracrine and autocrine messengers

NT act as 1st or 2nd messenger?

1st - they bind to receptors and generate electrical or biochemical signals in postsynaptic cells

What type of synapses allow bi-directional flow?

Electrical

At electrical synapses, cells are connected by what?

gap junctions

Gap junctions consist of 2 hemichannels called _____.

connexions

What allows the myocardial cells to depolarize synchronously?

intercalated discs in the heart that contain electrical synapses

All ionotropic receptors have ____ subunits whose arrangement defines a central pore.

4-5

When does ionotropic receptor activation cease?

When the NT dissociates from the receptor or when the receptor is desensitized

Ionotropic receptors participate in fast or slow synaptic responses?

Fast

What are metabotropic receptors?

7 transmembrane-spanning receptors coupled to heterotrimeric G proteins (GPCR)

Metabotropic receptors participate in ____responses compared to inotropic receptors.

slower (seconds to minutes); compared to milliseconds or faster

AChr, adrenergic receptors, GABAbR, opioid receptors, and 5-HT1R are all _____ receptors.

metabotropic

What receptors trigger biochemical cascade?

Metabotropic - tip it sounds like metabolism or metabolite... it activates enzymes

The presynaptic terminal of chemical synapses contain what 2 important organells?

Mitochondria Synaptic vesicles

What is mitochondria's job in presynaptic terminals?

provides ATP, biochemical intermediates, and enzymes for the syntehsis and degradation of NT

What is synaptic vesicles job in presynaptic terminals?

concentrate, store, and deliver NT at the synapse

Membrane depolarization causes _____ channels (N-type) to open, permitting Ca2+ ions to flow into the terminal.

Ca2+

Increased intracellular Ca2+ is sensed by _____ in the docking proteins complex. This triggers the fusion of vesicles with the presynaptic membrane. This process is _____.

synaptotagmin; exocytosis

NT molecules bind to either ____ or _____ receptors on the post-synaptic membrane, leading to a post-synaptic event.

ionotropic or metabotropic

Volatile anesthetics inhibit excitatory neurotransmission (via ___ and ____ receptors).

NMDA and nicotinic ACh

Volatile anesthetics enhance inhibitor neurotransmission (via ___ and ____ receptors).

GABA and glycine

What causes hyperpolarization?

outward current of K+, Cl= influx, closure of Ca2+ channels

What causes depolarizatin?

net inward current of: Na+ influx Ca2+ influx Reduced K+ efflux through leaky channels

Ionotropic receptor OR metabotropic receptor??? Conformational change sets in motion a biochemical cascade

Metabotropic

Ionotropic receptor OR metabotropic receptor??? Slower synaptic response

Metabotropic

Ionotropic receptor OR metabotropic receptor??? Muscarinic AChR

Metabotropic

Ionotropic receptor OR metabotropic receptor??? 5-HT3R

Ionotropic

Ionotropic receptor OR metabotropic receptor??? Conformational change gates a pore

Ionotropic

Ionotropic receptor OR metabotropic receptor??? Nicotinic AChR

Ionotropic

Ionotropic receptor OR metabotropic receptor??? Opioid Receptor

Metabotropic

Ionotropic receptor OR metabotropic receptor??? Fast synaptic response

ionotropic

List 2 gases that are unconventional NT.

NO CO

What structure connects cells at an electrical synapse?

Gap junctions (connexions form gap junctions)

Which protein in the docking complex is the calcium sensor?

Synaptotagmin

Name 3 signals that open pores in gated ion channels.

Membrane voltage (electrical), chemicals (ligands), and pressure (mechanical)

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional DOPAMINE

Biogenic Amine

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional VASOACTIVE INTESTINAL PEPTIDE (VIP)

Neuropeptide

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional OPIOIDS

Neuropeptide

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional NOREPINEPHRINE

Biogenic Amine

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional ANANDAMIDE

Nonconventional

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional GLUTAMATE

Amino Acid

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional NITRIC OXIDE

Nonconventional

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional GLYCINE

Amino Acid

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional SUBSTANCE P

Neuropeptide

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional GABA

Amino Acid

Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional SEROTONIN

Biogenic Amine

Where are nicotinic acetylcholine receptors NOT located? a. autonomic ganglia b. neuromuscular junction c. chromaffin cells in the adrenal medulla d. sinoatrial node

D - sinoatrial node

What is the primary NT of peripheral EFFERENT (motor) neural pathways?

Acetylcholine (ACh)

What role does Acetylcholine play in the CNS?

- the modulation of sleep - wakefulness (in the RAS) - learning - memory

Where does Acetylcholine synthesis occur?

In the presynaptic nerve terminal

T/F: Cholinergic receptors can be ionotropic or metabotropic.

True

Are nicotinic ACh receptors ionotropic or metabotropic?

ionotropic

Are muscarinic ACh receptors ionotropic or metabotropic?

metabotropic

Cholinergic describes neurons or synapses that use ____ as the neurotransmitter.

Acetylcholine

Acetylcholine is the primary NT of peripheral efferent or afferent neural pathways?

EFFERENT

List all the places ACh is a NT at: 1. 2. 3. 4. 5.

1. NMJ 2. Autonomic ganglia 3. Terminal synapses of parasympathetic postganglionic fibers 4. Few sympathetic postganglionic fibers (sweat glands) 5. NOn-neuronal cholinergic system (NNCS)

T/F: Only nicotinic receptors are expressed in the central neurons, not muscarinic receptors.

False - both are

What are the substrates of acetylcholine?

choline and acetyl-CoA

What is the rate-limiting factor for the availability of Acetylcholine?

The availability of its substrates (choline and acetyl-CoA)

How does glucose enter nerve terminals?

by passive transport (facilitated diffusion)

Glycolysis converts glucose to ______.

pyruvate

Where does glycolysis occur?

in the cytoplasm

An acetyl group from pyruvate is added to coenzyme A to produce _____.

acetyl-CoA

Choline is ______ transported into the presynaptic terminal.

actively

________ is the rate-limiting step in ACh synthesis.

Choline transport

What catalyzes the formation of ACh from acetyl-CoA + choline?

Choline acetyltransferase (ChAT)

Where is ACh stored?

In synaptic vesicles until release

How is ACh transported into vesciles?

By an H+-antiporter (exchanger)

_____ triggers vesicle fusion at the active zone, and ____ is released into the synaptic cleft by exocytosis.

Increased intracellular Ca2+; ACh

What hydrolyzes ACh? What is it hydorlyzed to?

Acetylcholinesterase (AChE); acetate + choline

What happens to the choline that is produced durign ACh hydrolysis?

It re-enters the nerve terminal and is reused for ACh synthesis

What is an antagonist of Ca2+ at the presynaptic nerve terminal?

Mg2+

Why does Mg2+ cause muscle weakness or potentiate NM block?

It is an antagonist of Ca2+ at the presynaptic nerve terminal

Nicotinic ACh recetpors (nAChR) are inotropic or metabotropic receptors?

Inotropic

T/F: nAChRs are nonselective anion channels.

F - nAChRs are nonselective cation channels.

Describe the structure of nAChRs.

They are pentameric complexes with 2 agonist binding sites - one at the extracellular 𝜶/ε interface of one 𝜶 subunit and the 𝜶/𝛅 interface of the other 𝜶 subunit

What is required to initiate the conformational change that opens the nAChR channels?

simultaneous binding of 2 ACh molecules to the alpha subunits

Where are NmAChRs found?

in skeletal muscle at the NMJ

Where are NnAChRs found?

in the autonomic ganglia, on the chromaffin cells of the adrenal medulla, and in the CNS

As their name implies, nAChR can be opened by the ____plant, _____.

tobacco plant, alkaloid nicotine

Muscarinic ACh receptors (mAChR) are inotropic or metabotropic receptors?

Metabotropic

Where are muscarinic AChRs found?

CNS, heart, smooth muscle, and glands of GI tract

_____ mediate most action of ACh in the CNS.

mAChR

Muscarinic AChRs are so named b/c they are activated by ____, a _____ found in a poisonous mushroom.

muscarine, a toxic alkaloid

How many types of mAChR have been identified?

Where are NM (nicotinic ACh) receptors found?

Skeletal muscle at NMJ

What is the signal transduction of NM (nicotinic ACh) receptors?

Opening of nonselective cation channels --> influx of Na

What is the response of activated NM (nicotinic ACh) receptors?

end-plate depolarization and skeletal muscle contraction

Where are NN (nicotinic ACh) receptors found?

Autonomic ganglia, adrenal medulla, CNS

Where are M1 (muscarinic ACh) receptors found?

autonomic ganglia CNA

Where are M2 (muscarinic ACh) receptors found?

Heart: nodal tissue Heart: cardiac muscle

Where are M3 (muscarinic ACh) receptors found?

Smooth muslce; GI

Where are M4 (muscarinic ACh) receptors found?

CNS

Where are M5 (muscarinic ACh) receptors found?

CNS

What muscarinic receptors are found in the heart?

What muscarinic receptors are found in the GI tract?

What is the signal transduction of NN (nicotinic ACh) receptors?

Opening of nonselective cation channels --> influx of sodium

What is the signal transduction of M1, M3, and M5 (muscarinic ACh) receptors?

Gq,11 --> PLC --> increased IP3 + increased DAG --> increased Ca2+ --> increased PKC ALL ODD MUSCARINIC ARE COUPLED TO GQ

What is the signal transduction of M2 and M4 (muscarinic ACh) receptors?

βᵞ subunit of Gi --> increased K+ channel (GIRK) opening Gi --> inhibition of AC --> decreased cAMP ALL EVEN MUSCARINIC ARE COUPLED TO Gi

What is the response of activated NN (nicotinic ACh) receptors?

Depolarization of post-synaptic post-ganglionic neuron Secretion of catecholamines Arousal, attention, analgesia

What is the response of activated M1 (muscarinic ACh) receptors?

Excitatory response Arousal, attention, analgesia

What is the response of activated M2 (muscarinic ACh) receptors?

Slowed spontaneous depolarization DECREASES chronotropy, contracitlity, and domotropy

What is the response of activated M3 (muscarinic ACh) receptors?

Contraction Increased salivary secretions

What is the response of activated M4 (muscarinic ACh) receptors?

Presynaptic autoreceptors --> negative feedback to supress ACh release

What is the response of activated M5 (muscarinic ACh) receptors?

Promotes dopamine release, dilation of cerebral arteries

Muscarinic AChR or Nicotinic AChR???? Binding of 2 Ach molecules for full activation

Nicotinic

Muscarinic AChR or Nicotinic AChR???? Ionotropic

Nicotinic

Muscarinic AChR or Nicotinic AChR???? NMJ

Nicotnic

Muscarinic AChR or Nicotinic AChR???? Slowed spontaneous depolarization of SA node

Muscarinic

Muscarinic AChR or Nicotinic AChR???? Coupled to heterotrimeric G protein

Muscarinic

Muscarinic AChR or Nicotinic AChR???? Secretion of catecholamines from adrenal medulla

Nicotonic

Muscarinic AChR or Nicotinic AChR???? Nonselective cation channel

Nicotinic

Muscarinic AChR or Nicotinic AChR???? Metabotropic

Muscarinic

Muscarinic AChR or Nicotinic AChR???? Presynaptic autoreceptors

muscarinic

Muscarinic AChR or Nicotinic AChR???? Airway smooth muscle

Muscarinic

The NMDA receptor has bindings sites for: (select 3) a. gamma-aminobutyric acid b. glutamate c. propofol d. ketamine e. magnesium f. calcium

B - glutamate d - ketamine e - magnesium

The amino acid NT include ____, ____, and _____.

gutamate, ᵧ-aminobutyric acid (GABA), glycine

_____ is the primary excitatory NT in the brain.

GLUTAMATE

What is the main inhibitory NT in the brain?

GABA

What is the primary inhibitor NT in teh spinal cord and lower brain stem?

GLYCINE

____ and ____ are interconvertible through Krebs cycle (aka tricarboxylic acid cycle) intermediates.

Gutamate and GABA

Are glutamate receptors inotropic or metabotropic?

they can be both

What receptors are a target for ketamine?

NMDA

What are the two ionotropic glutamate receptors?

NMDA and AMPA

What is neuronal injury initiated by excessive glutamate receptor activity called?

excitotoxicity

GABA receptors can be ionotropic and metabotropic. Which is which?

GABAa = ionotropic GABAb = metabotropic

Which receptor is a target for Benzos, propofol, etomidate, and volatiles?

GABAa

Is the glycine receptor ionotropic or metabotropic?

ionotropic

Is glutamate excitatory or inhibitory?

excitatory

Glutamatergic synapses exist throughout the ____.

CNS

What are excitatory responses to gluatmate?

motor neuron activation, pain pathway transmission, elevated pain sensation (hyperalgesia), memory formation, cerebral neurotoxicity

Is GABA inhibitory or excitatory?

Inhibitory

Most CNS ____ and ____ express GABA receptors; therefore, GABA receptors influence many neural circuits and functions.

neurons and astrocytes

GABA neurons play a role in what?

arousal and attention; memory formation; anxiety; sleep; muscle tone

Is glycine inhibitory or excitatory?

inhibitor

What type of cells form inhibitory glycinergic synapses upon alpha motor neurons?

Renshaw

Why myst glutamate be synthesized in the brain?

B/c it canNOT cross the BBB

How is glutamate converted to GABA?

By glutamic acid decarboxylase

IN one path for glutamate synthesis, _____ produced by the Krebs cycle serves as the substrate for GABA transaminase. What is the the product of transamination?

𝜶-ketoglutarate; glutamate

How is glutamine converted into glutamate?

By glutaminase on the mitochondiral membrane

What is the rate-limiting step in glutamate synthesis?

Glutaminase activity

Where is glutamate stored until release?

synpatic vesicles

______ reuptake glutamate from the synaptic cleft via glutamate transporters.

Glial cells (glutamate is converted into glutamine by the enzyme glutamine synthetase)

What are teh 3 types of ionotropic glutamate receptors?

1. N-methyl-D-aspartate (NMDA) 2. 𝜶-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) 3. Kainate

Where are NMDA and AMPAs both prevalently located?

hippocampus and cerebral cortex

Full activation of AMPA receptors requires waht?

binding of 2 glutamate molecules

AMPA receptors are non-selective cation channels that are highly permeable to ___ and poorly permeable to ___.

Na; Ca

AMPA are responsible for early post-synpatic membrane depolarization in response to _____ release.

glutamate

What plays a key role in AMPA desnsitization?

Phosphorylation

Full activation of NMDA receptors requires the binding of 2 ____, 2 _____ and a ______.

glutamates; glycine; depolarizing voltage change These are safety locks on the NMDA receptor - each must be met for full activation

NMDA receptors are non-selective cation channels that are highly permeable to ___ but permeable to ___.

Ca; Na (opposite of AMPA)

NMDAs are slower or faster gated than AMPA?

slower NMDAs are slower-gating (Delayed) excitatory synaptic transmission.

NMDA: a _____ binding site is located within the channel, this is also the binding site for ketamine.

phencyclidine (phenylcyclohexyl piperidine, PCP; "angel dust")

What are the 3 groups of metabotropic glutamate receptors?

1. 1 coupled to Gq and activate phospholipase C 2 & 3. coupled to Gi and prevent the formation of cAMP

Metabotropic glutamate receptors are widely distributed where?

in the brain at post and pre synaptic locations and on glial cells

What is long-term potentiation?

Ca+ influx through NMDA receptors plays a key role in many Ca- dependent processes, including the consolidation of short-term memories --> long term memories

What is apoptosis?

programmed cell death

What diseases is excitotoxicity implicated as a pathologic mechanism?

Huntington's, Alzheimer's, ALS, stroke and trauma, hyperalgesia, epilepsy

What are the three safety locks of NMDA receptors?

voltage-dependence 2 glutamate bindings 2 glycine bindings

Why do safety locks for NMDA receptors exist?

Hyperactivation would result in flooding of neurons by Ca2+ causing cell death

What catalyzes the decarboxylation of glutamate to GABA?

Glutamic acid decarboxylase

The amount of GABA in the CNS correlates to the amount of functional ____.

Glutamic acid decarboxylase (GAD)

Where does conversion of glutamine to glutamate occur?

mitochondria

What converts glutamine to glutamate?

glutaminase

How is GABA formed and where?

By the decarboxylation of glutamate; in the cytoplasm

T/F: GAD is not present in neurons using glutamate as a NT.

True

Is GABA recylced?

Yes

How are GABAa receptors activated?

the binding of 2 GABA molecules

GABA_ receptors are pentameric ligand-gated Cl- channels.

GABA _ receptors are 7-transmembrane G protein-coupled receptors.

Activation of GABAb generates inhibitory effects in post-synaptic neurons via second messenger systes involving: ____ ____ ____ ____

PLC adenylyl cyclase βᵞ unit opening of K+ channels βᵞ closing of Ca2+ channels

How is glycine formed?

From serine (an amino acid) in an enzyme-catalyzed reaction

______ is a co-activator of the NMDA receptor.

Glycine

Mutations of the glycine receptors are involved in rare neuro dx such as ____ or ____

human startle dx or hyperekplexia

GABAa OR NMDA?????? Excitatory responses

NMDA

GABAa OR NMDA?????? Flumazenil is antagonist

GABA

GABAa OR NMDA?????? Propofol binding site

GABA

GABAa OR NMDA?????? Benzo binding site

GABA

GABAa OR NMDA?????? Inhibitory response

GABA

GABAa OR NMDA?????? Mg ions block channel at resting membrane potential

NMDA

GABAa OR NMDA?????? KEtamine binding site

NMDA

GABAa OR NMDA?????? Glycine is a co-transmitter

NMDA

What is the primary inhibitory NT in the spinal cord?

Glycine

Which NT is associated w/ excitotoxicity?

Glutamate

WHich GABA receptor is metabotropic?

What 2 binding sites are located in the NMDA receptor channel (pore)?

Mg2+ and Ketamine/PCP

Glutamate is converted to GABA by what type of enzymatic reaction?

Decarboxylation

Which enzymes are required to degrade epinephrine to vanillylmandelic acid? (select 2) a. catechol-O-methyltransferase b. L-amino acid decarboxylase c. monomaine oxidase d. tyrosine hydroxylase

A and C

What are the 5 biogenic amine NT?

1. dopamine 2. norephinephrine 3. ephinephrine 4. serotonin 5. histamine

What are all teh biogenic amine NT derived from?

amino acids by enzymatic hydroxylation and decarboxylation

What 3 things are known as catecholamines?

dopamine, norepinephrine, epinephrine

______ is the rate limiting step in catecholamine biosynthesis.

Tyrosine hydroxylase

What 2 enzymes degrade NE and Epi?

1. monoamine oxidase (MAO) 2. catechol-O-methyltransferase (COMT)

What is the end-product of catecholamine metabolism?

Vanillylmandelic acid (VMA)

How is VMA eliminated?

urine

serotonin is synthesized from ____

tryptophan

What is the end product of serotonin metabolism?

5-hydroxyindoleacetic acid (5-HIAA)

How is 5-HIAA eliminated?

urine

Histamine is synthesized from _____

histidine

What physiologic responses do biogenic animes cause?

central control of cardiac function, BP, and metabolism; coordination of movement; cognitive function; regulation of appetite and feeding; sleep; behavior

Most biogenic amine NT receptors are _______ receptors. What is the exception?

metabotropic; ionotropic 5-HT3 serotonin receptor

All catecholamines are synthesized from ______.

tyrosine

Serotonin is synthesized from _______.

tryptophan

Histamine is synthesized from _______.

histidine

All biogenic amine NT are synthesized rom _______

amino acids

What 2 enzymatic reactions are common in the biosynthesis of biogenic amine NT?

Hydroxylation and decarboxylation

What occurs during hydroxylation?

An -OH group is added

What occurs during decarboxylation?

A -CO2 group is removed

If tyrosine supply is low, how can cells generate tyrosine?

From phenylalanine by hydroxylation (tip: [maybe??? lol] the alternate name for tyrosine is hydroxyphenylalanine)

Tyrosine is hydroxylated or decarboxylated by the enzyme tyrosine hydroxylase? What is formed?

HYDROXYLATED; L-DOPA

What is the rate-limiting step in catecholamine synthesis?

Tyrosine hydroxylation to L-DOPA

During catecholamine synthesis, tyrosine hydoxylase is subject to feedback inhibition by what?

Dopamine and NE

During catecholamine synthesis, is L-DOPA hydroxylated or decarboxylated by aromatic L-amino acid decarboxylase? What is the result?

Decarboxylated; dopamine

After Dopamine is formed from L-DOPA where does it go?

It is transported into vesicles by an H+-antiporter. If the neuron is dopaminergic, the path stops here.

In nonadrenergic and adrenergic neurons or chromaffin cells, the path of catecholamine synthesis continues after Dopamine formation. In the storage vesicles, does hydroxylation or decarboxylation of the dopamine occur? What results?

Hydroxylation (by dopamine-β-hydroxylase); Norepinephrine

During catecholamine synthesis, in adrenergic cells and neurons, norepinephrine moves out of the vesicles to where? What does it encounter?

cytoplasm; phenylethanolamine-N-methyltransferase (PNMT)

PNMT catalyzes the ______ of NE to form ______.

methylation (CH3); epinephrine

Put these in order for which they are created: Norepinephrine, Dopamine, and Epinehprine

Dopamine --> Norepinephrine --> Epinephrine

What 2 enzymes metabolize catecholamines?

Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)

____ is a mitochondrial outer-membrane enzyme found in most neurons and other tissues.

MAO

What two isoforms does MAO exist in?

MAO-A and MAO-B

What does MAO-A preferentially degrade?

Dopamine, Epi, serotonin

what does MAO-B degrade?

Dopamine more rapidly than serotonin or NE

_____ is a relatively nonspecific cytosolic enzyme found in endothelial cells, the heart, kidneys, liver, smooth muscle, and glial cells.

COMT

What is the end-product of catecholamien metabolism?

Vanillymandelic acid

How is pheochromocytoma diagnosis made?

biochemical determination of free catecholamine concentration and catecholamine metabolites (VMA) in urine

What is the major metabolite of dopamine? How is Dopamine metabolized?

Homovanillic acid (HVA); MAO and COMT

Does serotonin cross the BBB?

No (brain must synthesize its own)

What is the substrate for serotonin synthesis?

Dietary L-tryptophan

What is serotonin metabolized to?

5-hydroxyindoleacetic acid (5-HIAA)

How is 5-HIAA excreted? What do high levels in the urine show?

urine; consistent w/ carcinoid tumors

______ is an imidazole amine consisting of an imidazole ring and an amino group connected by 2 methylene groups.

Histamine

How is histamine synthesized in the periphery?

By mast cells and basophils

Does histamine cross the BBB?

The brain synthesizes its own histamine from _______.

L-histidine (an amino acid)

Histidine is _______ to form histamine

decarboxylated

What metabolizes histamine?

oxidative paths in liver

What is one major metabolite of histamine that can be measured in the urine to determine the amount of histamien that has been released systemically?

imidazole acetic acid

All catecholamine NT are derived from which amino acid?

L-tyrosine

What enxymatic reaction is present in ALL biogenic amine NT biosynthesis?

Decarboxylation

Match each adrenergic receptor with the G protein alpha subunit coupled to the receptor: alpha 2; alpha 1; beta & Gq, Gi, Gs

Alpha-2 Receptor - Gi Alpha-1 Receptor - Gq Beta Receptor - Gs

How are biogenic amine NT removed from the synaptic cleft?

By reuptake into the presynaptic terminal or uptake into non-neuronal cells and organs

What are the 3 main classes adrenergic receptors can be divided into?

Alpha-1 Alpha-2 Beta

Derangements of serotonergic paths contribute to what?

Anxiety, depression, mania, schizophrenia

What serotonin receptor is the target of antagonists for PONV and Chemo-induced N/V?

5-HT3

What role do serotonergic neurons play?

sleep and wakefulness, emotions, cognition, and CV, respiratory, and intestional activitives

What role do histaminergic neurons play?

arousal and attention, memory, learning, mood

About ___% of the dopamine entering the terminal is recycled into vesicles by the H+-antiporter. The remaining ___% is destroyed by the mitochondrial enzyme MAO.

50%; 50%

Where is the largest concentration of dopaminergic neurons in the brain?

the substantia nigra

The dopaminergic neurons in the substantia nigra are crucial for what?

coordinating movements

Degeneration of Dopaminergic neurons in the substantia nigra causes _______.

Parkinson's disease

Besides the substantia nigra, other dopaminergic neurons in the CNS are involved with ______ and ______.

motivation and reward (limbic system) and cognitive functions such as spatial learning and memory (prefrontal cortext)

How many types of dopamine receptors are there?

The D1-like dopamine receptors are ___ and ____. They activate what?

D1 and D5; PKA through adenylyl cyclase and cAMP, and PKC through PLC

The D2-like dopamine receptors are ___, _____, and ____. They inhibit what?

D2, D3, and D4; inhibit adenylyl cyclase and thus reduce PKA activity which ultimately leads to decreased neuronal excitability

What is implicated in the pathogensis of schizophrenia?

Overactive D2-like receptors

Where is the major concentration of noradrenergic neurons in the CNS?

Locus coeruleus in the pons

Noradrenergic neurons from the locus coeruleus reach the ___, ____, ____ and ____.

thalamus, hypothalamus, limbic system, and cerebral cortex

What the noradrenergic projections important in?

arousal, attention (Vigilance ), and feeding behaviors

2 major groups of adrenergic (epi) neurons have been identified in the CNS: 1. _________________ 2. _________________

1. Rostral ventrolateral medulla 2. Nucleus tractus solitarius

In the peripheral nervous system, NE is released from where?

from most post-ganglionic symapthetic neurons onto the target tissues

In the peripheral nervous system, Epi is released from where?

chromaffin cells of the adrenal medulla into the circulation in response to stress

All adrenergic receptors are metabotropic or ionotropic?

Metabotropic

Adrenergic receptor classes are distinguished by their relative sensitivity to _____.

Isoproterenol (N-isopropyl-noradrenaline)

Isoproterenol activates ____ receptors, whereas ____ receptors are poorly activated by isoproterenol.

Beta; alpha

NE preferentially binds to what receptors?

A1, A2, and B1

Activation of ______ results in inhibition of NE release

presynaptic alpha-2

Epi is an agonist of what receptors?

alpha and beta

At low concentrations Epi has predominately ____ effects, while at higher concentrations, its ___ effects become more pronounced.

Beta; A1

Serotonergic neurons are clustered in several ______.

midline raphe nuclei

Rostral raphe nuclei project to the ___, ___, and ____.

thalamus, limbic system, and cortex

Caudal raphe nuclei project to the _______ and _____

spinal cord; within the brain stem

How many of the 4 main classes of serotonin receptors are metabotropic?

5-HT1 receptors inhibit

adneylyl cyclase

5-HT2 receptors usually stimulate ___ and _____

stimulate PLC and mobilization of Ca2+

5-HT4 receptors stimulate ______

adenylyl cylcase and pKA activation

Activation of 5-HT3 receptors leads to rapid _____

membrane depolarization

How do 5-HT3 antagonits exert their effect?

they block receptors in the area postrema as well as in the vagus nerve, which normally activates the vomiting center

Where is the highest density of histamine-containing neurons found?

in the tuberomammillary region of the hypothalamus

Gs, Gi, or Gq??????? 5-HT4

Gs, Gi, or Gq??????? Alpha-2

Gs, Gi, or Gq??????? Alpha-1

Gs, Gi, or Gq??????? D1

Gs, Gi, or Gq??????? 5-HT1

Gs, Gi, or Gq??????? Beta

Gs, Gi, or Gq??????? 5-HT2

Gs, Gi, or Gq??????? D2

The largest concentration of dopaminergic neurons is in the brain is in what strucutre?

Substantia nigra

What cells in the adrenal medulla release Epi into the circulation?

chromaffin

Zofran targets which specific serotonin receptor?

5-HT3

What is the substrate for nitric oxide synthase? a. L-citrulline b. Nitric oxide c. L-arginine d. Guanosine triphosphate

What are the purinergic NT?

ATP, ADP, and adenosine

T/F: Purinergic receptors are ionotropic.

False - purinergic receptors are both ionotropic and metabotropic

ALl neuropeptides act on what receptors? and what happens?

metabotropic; they induce alterations in teh excitability of post-synaptic cells

____ is a universal intercellular messenger, acting as both an autocrine and paracrine signaling molecule.

At body temp, NO is a small, ______ that easily permeates lipid membranes, "soaking" the surrounding tissue cell.

lipid-soluble gas

What does nitric oxide synthase do?

converts L-arginine to L-citrulline and NO

Many effects of NO are mediated locally by soluble guanylyl cyclase which produces ____ from GTP.

cGMP

NO plays a role in central sensitization to _____

pain

What roles do purine and pyrimidine nucleotides do?

- precursors of DNA and RNA - components of enzymes - energy currency - allosteric modulators of enzymes - second messengers - auto-and paracrine first messengers

Purine bases are _____ and ______

adenine (A) and guanosine (G)

What are two examples of purines?

theophylline and caffeine

Pyrimidine bases are ___, ____ and ____

cytosine (C), thymidine (T), and uracil (U)

______ acid is a pyrimidine.

Barbituric

What is a nucleotide composed of?

A 5-carbon sugar(pentose), nitrogenous base, and at least 1 phosphate group

ATP, ADP and AMP and GTP, GDP, and GMP are pyrimidine or purine nucleotides?

Purine

UTP, UDP, and UMP and CTP, CDP, CMP are pyrimidine or purine nucleotides?

Pyrimidine

What is a nucleoside composed of?

A pentose and a nitrogenous base, with NO phosphate groups (the phosphate groups differentiate a nucleoside and nucleotide)

What are the main purinergic transmitters?

ATP, ADP, and adenosine

What purinergic transmitter is frequently coreleased with other transmitters?

ATP

Adenosine is generated from ___ in the extracellular space (ex: synaptic cleft) by an enzyme, _____.

ATP; ectonucleotidase

Adenosine plays a role in the _____ state.

sleep/wake

Increased or decreased adenosine levels promote sleep?

Increased

Increased or decreased adenosine promotes wakefulness?

Decreased

Adenosine plays a crucial role in protecting tissues from damage. A strong ___ in adenosine levels. in the ECF is an emergency signal indicating an acute oxygen deficiency (CVA, angina, MI)

INCREASE

What dysrhythmia is adenosine indicated for? What does it do?

SVT; it stops the heart briefly to allow the SA node to assume the role of the dominant pacemaker

What are purinergic NT metabolized to?

5'-AMP

What are the two families of purinergic receptors?

P1 and P2

Are P1 and P2Y receptors metabotropic or ionotropic?

Metabotropic

Is P2X metabotropic or ionotropic?

Ionotropic

What role do P2X receptors play on sensory nerves?

Detect and signal tissue damage and inflammation

Some ____ receptors are found on the presynaptic membrane and serve to suppress ATP release by negative feedback through Gi paths.

P2Y

PLT aggregation is induced by ADP binding to _____ receptors.

P2Y

How does NO arise?

From the oxidation. of the guanidino group of L-arginine

What does generation of NO require?

NADPH, molecular oxygen, and is catalyzed by a family of oxygenases known as NO synthases

How many families of nitric oxide synthase are there?

What families of nitric oxide synthase are calcium-dependent enzymes?

NOS1 and NOS3

NO is both an ____ messenger and a ____ gas.

endogenous; cytotoxic

NO effects depend on what?

Its tissue concentration

At low concentrations, what does NO function as?

A signaling molecule and interacts w/ a cytoplasmic receptor, soluble guanylyl cyclase (sGC)

At high concentrations, NO exhibits what effects?

Signaling effects by modifying proteins by nonenzymatic S-ntirosylation

At extremely high concentrations of NO, what dominates?

the cytotoxic effects ... overstimulation of NO formation plays a role in life-threatening evens such as CVA and endotoxin shock

The _____ complex activates NOS.

Ca2+-calmodulin

Activation of NOS results in the formation of ___ and ___ from L-arginine.

NO and citrulline

NO interacts with the heme moiety of ______ (sGC).

soluble guanylate cyclase

sGC activated by NO catalyzes the conversion of ___ to ____ in teh post-synaptic neuron.

GTP --> cGMP

Retrograde diffusion of NO into the pre-synatpic terminal has a ____ feedback effect.

positive

NO is a highly reactive free radical wiht a half-life of how long?

a few seconds

When are functions of NO terminated?

When NO is converted to nitrities and nitrates by oxygen and water

What roles do NO play?

sleep, controls normal feeding behavior, role in GI function

What is long-term potentiation?

An activity-dependent increase in synaptic efficacy

What is long-term depression?

A decrease in synpatic efficacy due to prolonged "weak" stimulation of a synapse

NO is synthesized and released by endothelial cells and thus has an important role in the control of ______.

vascular tone

Are GTP and ATP classified as purines or pyrimidines?

Purines

What enzyme converts ATP to adenosine in the synaptic cleft?

Ectonucleotidase

Are all neuropeptide receptors ionotropic or metabotropic?

Metabotropic

What signaling complex activates nNOS?

Ca2+/CaM (calmodulin)

An activity-dependent increase. in synaptic efficacy is called:

Long-term potentiation (LTP)

What cytosolic heme- containing enzyme is activated by NO?

Soluble guanylyl cyclase (sCG)

The receptor for insulin is a: a. receptor guanylylcyclase b. receptor tyrosine kinase c. tyrosine kinase-associated receptor d. receptor serine/threonine kinase

What are the 5 major categories of enzyme-linked receptors?

1. receptor guanylylcyclase 2. receptor tyrosine kinases 3. tyrosine kinase-associted receptors 4. receptor serine/threonine kinases 5. receptor tyrosine phosphates

Receptor _____ convert GTP to cGMP.

guanylyl cyclases

What is the largest family of enzyme-linked receptors?

Receptor tyrosine kinases

____ and ____ are ligands to RTKs.

Insulin and growth factors

Mutations. in________ are associated with. a wide variety of cancers.

receptor tyrosine kinases (RTK)

T/F: Tyrosine kinase associated receptors do not have intrinsic enzyme activity.

True

Receptor _____ are important mediators of cell growth and differentiation.

serine-threonine kinase

Transmembrane catalytic receptors are also known as ______ receptors

enzyme-linked

What do transmembrane catalytic receptors do?

transduce an extracellular ligand-binding interaction into an intracellular effect by activating a "linked" enzymatic domain

Enzyme-Linked Receptors: ________ contain a cytosolic domain that catalyzes the formation of cGMP from GTP.

Receptor Guanylyl Cyclases

Enzyme-Linked Receptors: ______ are the largest group to transmembrane catalytic receptors.

Receptor Tyrosine Kinases

Enzyme-Linked Receptors: ________ lack inherent catalytic activity. These receptors recruit active cytosolic signaling proteins in a ligand-dependent manner.

Tyrosine Kinase Associated receptors

Enzyme-Linked Receptors: ______ have intrinisic catalytic activity and phosphorylate serine and threonine residues on target cytosolic proteins.

Receptor serin/threonine kinases

Enzyme-Linked Receptors: _______ dephosphorylate tyrosine residues on other transmembrane receptors or on cytosolic proteins. They play important roles in cells of the immune system.

Receptor Tyrosine Pohsphates

Transmembrane catalytic receptors are ____ membrane-spanning proteins.

single

What are. theligands for enzyme-linked receptors?

Polypeptides and larger proteins

____ catalyzes teh metabolism of cGMP to 5'-GMP, terminating the actino. ofcGMP.

PDE5

____, ____, and ____ are ligands for receptor guanylyl cyclases.

ANP, BNP, and CNP

_______, a recombinant version of native natriuretic peptides, is used in the treatment of decompnesated HF.

Nesiritide

T/F: RTKs always work in pairs.

True

What tissues express higher levels of the insuline receptor?

energy-storing tissues of liver, muscle, and adipocytes

Obese people have varying degrees of _____ resistance.

leptin

Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors???? Tyrosine kinase activity is built-in to the receptor

Receptor tyrosine kinases

Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors???? Insulin receptor

Receptor tyrosine kinases

Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors???? ANP is a ligand

Receptor guanylyl cyclases

Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors???? Cell differntiation

serine-threonin kinase receptors

Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors???? TGF-β is a ligand

Serine-threonin kinase receptors

Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors???? JAK-STAT system is downstream target

Tyrosine kinase-associated receptors

Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors???? Lepitn receptor

Tyrosine kinase-associated receptors

Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors???? GTP to cGMP

Receptor guanylyl cyclases

Which signaling molecules bind to nuclear receptors (Select 3)? a. Ach b. Testosterone c. Vit D d. Erythropoietin e. Triiodothyronine f. Gamma-aminobutyric acid

B, C, E

Most chemical signals bind. to receptors where?

transmembrane

________ complexes are activated transcription factors that regulate the expression of target genes in the DNA.

Ligated (ligand-bound) nuclear receptor complexes

The intracellular receptor family includes receptors for ____,____,___,___, and ____.

steroid hormones prostaglandins Vit d thyroid hormones retinoic acid

_______ are activated transcription factors that bind. in a highly specific manner. to short DNA sequences called hormone response elements.

Ligand-bound nuclear receptors

_______ increase basal metabolic rate by stimulating futile cycles of catabolism and anabolism.

Thyroid hormones

What are. the2 subfamilies of nuclear receptors?

1. receptors for steroid hormones 2. receptors for retinoic acid, thyroid hormone, and Vit D

Steroid hormone receptors are ______

homodimers (e.g., PR-PR for progesterone)

Receptors for retinoic acid, thyroid hormones, and Vit D form heterodimers with the _______ receptor (RXR).

retinoic acid receptor

Preferred Ligand: 17β-estradiol Receptor/Transcription Factor: _______

Estrogen Receptor

Preferred Ligand: Progesterone Receptor/Transcription Factor: _______

Progesterone Receptor

Preferred Ligand: Testosterone Receptor/Transcription Factor: _______

Androgen Receptor

Preferred Ligand: Cortisol Receptor/Transcription Factor: _______

Glucocorticoid Receptor

Preferred Ligand: Aldosterone Receptor/Transcription Factor: _______

Mineralocorticoid receptor

Preferred Ligand: All-trans-retinoic acid Receptor/Transcription Factor: _______

Retionic acid receptor

Preferred Ligand: 9-cis-retinoic acid Receptor/Transcription Factor: _______

Retinoid X Receptor

Preferred Ligand: Triiodothyroinine (T3) Receptor/Transcription Factor: _______

Thyroid hormone receptor

Preferred Ligand: 1,25-dihydroxycholecalciferol (D3) Receptor/Transcription Factor: _______

Vitamin D Receptor

____, ____, and _____ receptors are mainly solbule cytoplasmic receptors.

Glycocorticoid, mineralocorticoid, and androgen

_____ and ____ are primarily soluble nuclear receptors.

Estrogen and progesterone

INtracellular receptors are also called ____ receptors

Nuclear

What nuclear receptors are bound. to DNA in the nucleus?

Retinoic acid, thyroid, and Vit D

_____ nuclear receptors are frequently complexed to chaperone ("heat shock") proteins.

Cytoplasmic

T/F: Thyroid hormones have effects. onvirtually every cell in the body.

True

Free thyroid hormone, T3 and T4, enters the cell how?

Through passive diffusion and active transport

In the cell, T4 is usually converted to ____ by a ____.

T3; deiodinase

Does the thyroid receptor in the nucleus have a greater affinity for T3 or T4?

T3 (10x greater affinity)

T3 is responsible for ___% of the occupancy. of thyroid receptors in the euthyroid state.

Ligand-bound ____ complexes bind to thyroid response elements on DNA and act as transcription activators or repressors in a tissue-specific fashion.

TR-RXR

How do thyroid hormones increase basal metabolic rate?

By stimulating futile cycles of both catbolism and anabolism

What stage of life are thyroid hormones essential for normal human development?

Infancy

What causes congenital hypothyroidism?

Congenital deficiency of iodine and thus thyroid hormone during infancy

If hypothyroidism is recognized and corrected within _____ after birth, then development - including mental development. -can proceed almost normally.

7 -14 days

THe DNA-binding site for ligand-bound nuclear receptors. iscalled an:

Hormone response element

An unoccupied cytoplasmic intracellular receptor is frequently complexed to a/n:

Chaperone protein (heat shock protein)

An unoccupied cytoplasmic intracellular receptor is frequently complexed to a/n:

Chaperone protein (heat shock protein)

WHat syndrome is associated with congenital hypothyroidism?

Cretinism

Which statement is NOT a feature of cell death by apoptosis? a. apoptosis is genetically programmed b. cells shrink during apoptosis c. plasma membranes are intact during apoptosis d. inflammation in surrounding tissues is common during apoptosis

What happens during necrosis of the cell: Cells swell or shrinks?? What happens to DNA? What happens to plasma membranes? What happens to cell contents? What happens to adjacent tissues?

Cell swells DNA condenses and dissolves Membranes are disrupted Contents dissolve and leak out Adjacent tissues undergo inflammatory process

What is necrosis of the cell?

Cell death. by uncontrolled chaotic cellular events in response to cell injury

What. is apoptosis of the celll?

Genetically controlled and programmed cell death pathways

What happens during apoptosis of the cell: Cells swell or shrinks?? What happens to DNA? What happens to plasma membranes? What happens to cell contents? What happens to adjacent tissues?

-Cells shrink -Nucleus is fragmented -Membranes are intact -Contents are usually intact & components are packaged into"bite-sized" apoptosomes and digested by phagocytosis -No inflammation occurs in surrounding tissues

T/F: Apoptosis death is normal.

True

What 2 paths initiate apoptosis?

1. intrinsic - mitochondrial path 2. extrinsic - death receptor-initiated path

During apoptosis, the intrinsic and extrinsic paths converge on. the____ pathway.

Effector (executioner)

What drugs cause apoptosis?

Almost all chemo drugs cause apoptosis of cancer cells

Excessive levels of ____ lead to neuronal injury or neuronal death by apoptosis.

Ca2+

What are the 3 forms of cell death?

Necrosis, apoptosis, and autophagic

When does autophagic death occur?

If apoptosis is blocked or defective

Cell death: Necrosis or Apoptosis??? Process is uncontrolled

Necrosis

Cell death: Necrosis or Apoptosis??? Process is genetically programmed

Apoptosis

Cell death: Necrosis or Apoptosis??? Cell enlarges and swells

Necrosis

Cell death: Necrosis or Apoptosis??? Cell is reduced and shrinks

Apoptosis

Cell death: Necrosis or Apoptosis??? Nucleus pyknosis --> karyolysis

Necrosis

Cell death: Necrosis or Apoptosis??? Nucleus fragmentation into nucleosome sized fragments

Apoptosis

Cell death: Necrosis or Apoptosis??? Plasma membrane is disrupted

Necrosis

Cell death: Necrosis or Apoptosis??? Plasma membrane is intact; yet altered structure can occur (especially orientation of lipids)

Apoptosis

Cell death: Necrosis or Apoptosis??? Cell contents undergo enzymatic digestion and may leak out of cell

Necrosis

Cell death: Necrosis or Apoptosis??? Cell contents are intact. andmay be released in apoptotic bodies

Apoptosis

Cell death: Necrosis or Apoptosis??? Adjacent inflammation frequently occurs

Necrosis

Cell death: Necrosis or Apoptosis??? Adjacent inflammation does not occur

Apoptosis

In adults, billions of cells die each hour. in tissues such as the ___ and ____ and are replaced by new cells.

Intestine and bone marrow

The programmed destruction. ofcells during ____ is crucial to normal growth and development.

Embryogenesis

DNA damage by _____, ____, and ______ will stimulate apoptosis if the insult is mild. Larger does of the same stimuli may lead to necrosis.

radiation, cytotoxic anticancer drugs, hypoxia

What 3 neurodegenerative diseases cause accumulation. of misfolded proteins that lead to apoptosis?

Alzheimer's, Huntington's and Parkinson's

What are the main biochemical features of apoptosis?

1. activation. of caspases 2. cell components break into fragments 3. membrane alteration. and recognition by phagocytes

What 2 families of proteins are key regulators of apoptosis?

Caspases and B-cell lymphoma proteins

What are the initiator caspases?

CAS-2, -8,-9, -10

What happens after initiator caspases are activated?

Initiator caspases dimerize and undergo proteolytic cleavage from a procaspase to the active caspase

What are the effector (executioner) caspases?

CAS-3, -7

How are effector caspases activated?

By the proteolytic attack of initiator caspases

What. isthe major mechanism of apoptosis in all mammalian cells?

The mitochondiral pathway

Apoptosis (Mitochondrial Path): Damage to mitochondria by ____ or ____ result. in the opening of large pores (called ____ channels) in the mitochondrial inner membrane.

reactive oxygen species (ROS); increases. in intracellular Ca2+; Bax/Bak channels

Apoptosis (Mitochondrial Path): What resides in the cytoplasm and mitochondrial membranes that keeps Bax/Bak in check in normal healthy cells?

Bcl-2

Apoptosis (Mitochondrial Path): After the mitochondria is damaged and pores are opened, what happens?

Cytochrome C and other proteins leak through the channels; mitochondria swell and may rupture

Apoptosis (Mitochondrial Path): The _____ activates caspase-9 and commits the cell to apoptosis.

apoptosome

Apoptosis (Death Receptor-Initiated): Extracellular signals bind to. a________ receptor.

trimeric transmembrane death receptor

Apoptosis (Death Receptor-Initiated): The cytosolic portion of the death receptor has a death domain that recruits what?

Several molecules of procaspase-8

Apoptosis (Death Receptor-Initiated): The recruited procaspase-8 aggregate undergoes autoproteolytic cleavage releasing ______.

active caspase-8

Apoptosis (Executioner [death] Path): Caspase-9 from. the____ path and caspase-8 from the ____ path converge upon executioner caspases __ and ___.

intrinsic; extrinsic; -3 and -7

What do executioner caspases do?

They are proteolytic enzymes that degrade cellular components - especially. the nucleus- into small fragments

What engulfs and processed apoptotic bodies?

Phagocytes

How quickly does phagocytosis of apoptoic cells occur?

Within minutes (so it does it w/o leaving a trace and w/o causing inflammation)

What. is signal for phagocytes to engulf the cells during apoptosis?

The phosphatidylserine phospholipid that is flipped to the outer leaflet of the membrane by caspases

Which protein keeps mitochondrial Bax/Bak pores in check. in healthy cells?

Bcl-2

Do most chemo durgs cause necrosis or apoptosis?

Apoptosis

What type. of cell digests apoptotic bodies?

Phagocytes

Intrinsic Apoptic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway??? Apoptosome activates caspase-9

Intrinsic

Intrinsic Apoptic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway??? Death pathway

Execution

Intrinsic Apoptic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway??? Caspase-8

Extrinsic

Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway??? Cell components. are packed into bite-sized apoptotic bodies

Execution

Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway??? Mitochondria initiate

Intrinsic

Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway??? Death Receptors initiate

Extrinsic

Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway??? Caspase-3 and Caspase-7

Execution

Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway??? Bax/Bak channel

Intrinsic

In the presynaptic nerve terminal, opioid-activated G protein βᵞ subunits block: a. voltage-gated Ca2+ channels b. voltage-gated Na channels c. voltage-gated K+ channels d. voltage-gated Cl- channels

A - Ca2+ channels

B1 adrenoreceptor stimulation of cardiac myocytes produces positive chronotropic, dromotropic, inotropic, and lustiropic effects by ____ mediated signal transduction paths.

cAMP

Many signals. at endothelial cells lead to the production of ____ and ___

NO and vasodilation

Opioids exert _____ synaptic inhibitory responses in neurons through _____ receptor signal transduction paths.

pre and post; G protein-coupled

What plays a key role. inwater regulation at the terminal nephron?

Vasopressin (Arginine Vasopressin [AVP]) and ADH

What. is the sole enzyme for terminating cyclic nucleotide signals?

Cyclic nucleotide phosphodiesterases (PDE)

Positive inotropy = ____

contractility

Positive lusitropy = ______

relaxation

Positive chronotropy = _____

Positive dromotropy = ______

conduction velocity

Stimulation of B1 G protein-coupled receptors on cardiac myocytes activates ____ and increases intracellular ___.

adenylyl cyclase; cAMP

After B1 stimulation, High levels of cAMP activate ____

protein kinase A (PKA)

The medications, ___, ___, ___ and ____ donate NO directly to vascular smooth muscle cells, leading to relaxation and vasodilations.

Nitroglycerin, sodium nitroprusside, and isosorbide dinitrate

What are the 4 families of opioid receptors?

1. Mu 2. Delta 3. Kappa 4. Nocicpetin

Opioids: In ___synpatic neurons, Gβᵞ subunits block voltage-gated Ca2+ channels.

Pre

Vasopressin plays a role in BP control at what 2 tissues?

Blood vessels and nephrons

Vasopressin binds to ____ receptors on the basolateral membrane, activating the heterotrimeric G_ protein.

g protein-coupled V2; S

PKA activation from Vasopressin does what?

Phosphorylates the water channel aquaporin 2 and activates transport. and fusion (exocytosis) of aquaporin-containing vesicles into the apical membrane

Vasopressin: Increased APQ2 in the apical membrane _____ water reabsorption.

Increases

Vasopressin binds to ___ receptors on vascular smooth muscle.

What. is a phosphodiesterase?

A hydrolase that breaks a phophodiester bond

When does a phosphodiester bond happen?

When 2 hydroxyl groups of phosphoric acid (H3PO4) react w/ 2 hydroxyl groups attached to carbons to form 2 ester bonds

______ form the backbone of DNA and RNA.

Phosphodiester bonds

How many families of phosphodiesterases are there?

PDE__ is nonselective for cAMP and cGMP, but binds to cAMP w/ 10x the affinity of cGMP binding.

Where is PDE3 found?

Heart, vascular and placental smooth muscle, and tissues important in energy homeostasis (liver, pancreatic beta cells, adipocytes)

Name 2 selective PDE3 inhibitors.

Milrinone and (in)amrinone

T/F: 2nd messengers are tissue specific.

True

PDE3 inhibitors ___ cAMP levels

increase

What are the outcomes of PDE3 inhibitors?

Positive chronotropy, dromotropy, inotropy, and lustiropy & vasodilation

What is Milrinone used for?

PHTN, cerebral vasospasm after aneurysmal subarachnoid hemorrhage, neonatal septic shock

How is milrinone eliminated?

REnal excretion

PDE__ is cGMP selective.

PDE5

Where is PDE5 found? Where. isthe highest concentration?

tissues throughout the body; Corpus cavernosus (penis & clitoris), vascular smooth muscle, and PLT

Name 3 PDE5 inhibitors.

Sildenafil, Vardenafil, Tadalafil

What are PDE5 inhibitors used for?

Erectile dysfunction, PHTN, high-altitude sickness, memory dysfunction

How are PDE5 inhibitors metabolzied?

by CYP450 in liver

PDE__ is cAMP selective.

What does PDE4 do?

MOdulates B2-adrenergic responses in pulmonary smooth muscle

Name 1 PDE4 med. What is it used for?

Roflumilast; COPD

What are weak, nonselective inhibitors of PDE?

Methylxanthines (caffeine and theopylline)

PDE3, PDE4, or PDE5??? Nonselective for cAMP and cGMP

PDE3, PDE4, or PDE5??? cAMP selective

PDE3, PDE4, or PDE5??? Milrinone is. aninhibitor

PDE3, PDE4, or PDE5??? Inhibitors. are metabolized by CYP450 3A4

PDE3, PDE4, or PDE5??? Sildenafil is an inhibitor

PDE3, PDE4, or PDE5??? cGMP selective

PDE3, PDE4, or PDE5??? Inhibitors are called inodilators

PDE3, PDE4, or PDE5??? Roflumilast is an inhbiitor

PDE3, PDE4, or PDE5??? Modulates B2 responses in pulmonary smooth muscle

Inhibition. of SRCA2 is relieved. by phosphorylation of?

Phospholamban

Endothelial nitric oxide synthase (eNOS) is activated by?

Ca2+CaM complex

Water reabsorption in principal cells of the collecting duct is increased by the insertion of what protein into the apical membrane?

Aquaporin 2 (APQ2)

What are the synonyms for Vasopressin?

- arginine vasopressin (AVP) - antidiuretic hormone (ADH)

Which is NOT a division of the ANS? A. sympathetic B. somatic C. parasympathetic D. enteric

The visceral nervous system is synonymous with. the ____ nervous system.

autonomic

What. arethe 3 divisions of the ANS?

sympathetic nervous system, parasympathetic nervous system, and enteric nervous system

Where does the ANS proide neural control to?Where does it not?

All parts of the body except skeletal muscle

____ nervous system is a major player. in homeostasis.

Autonomic

Central nervous system = ____ + _____

brain + spinal cord

Peripheral nervous system = ___ + ____

12 pairs of CN + 31 pairs. of spinal nerves

Voluntary control of skeletal muscle is the _____

somatic

Involuntary control of glands and smooth muscle is the ____

autonomic

Why is CN2 part of the CNS structuarlly?

It is covered in 3 meningeal layers

What do somatic nervers innervate?

Musculoskeletal strucutres and sensory organs of the skin

What do autonomic nerves innervate?

Smooth muscle, cardiac muscle, and glands

____ results in the absence of autonomic tone to a particular organ.

Denervation

Which anatomic part of the nervous system is surrounded and covered by the meninges?

CNS

Which type of muscle does NOT receive ANS signals?

Skeletal muscle

Sympathetic or Parasympathetic??? Miosis

Parasympathetic

Sympathetic or Parasympathetic??? Mass Discharge

Sympathetic

Sympathetic or Parasympathetic??? Artery tone

Sympathetic

Sympathetic or Parasympathetic??? Accommodation. inthe eye

Parasympathetic

What are the 3 forms extracellular signals take?

1. chemical 2. electrical 3. mechanical

What are thh 3 major categories of membrane-bound receptors?

1. Ion channels 2. G protein-coupled receptors 3. Enzyme-linked receptors

Where are intracellular receptors located?

The cytoplasm or nucleoplasm

____ is. theprocess by whihc a cell converts this extracellular signal into an intracellular response.

Signal transduction

T/F: An ion channel is open or closed.

True

What. are the 2 ways in which a GPCR can work?

1. opening or closing an ion channel 2. activating or inhibiting enzyme inside the cell

When an enzyme-linked receptor is at rest, the catalytic domain is inactive. oractive?

Inactive

The insulin receptor in skeletal muscle being linked to an enzyme called tyrosine kinase is an example. of ______ receptors.

enzyme-linked

Steroids bind to receptors in the ____. Ths is an example of ____ receptors.

cytoplasm; intracellular

Thyroid hormones bind to receptors in the ____. Ths is an example of ____ receptors.

nucleus; intracellular

Ion channel, GPCR, Enzyme-linked, or Intracellular????? B1 Receptor

GPCR

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Alpha or beta-gamma subunit opens or closes an ion channel

GPCR

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Thyroid hormone receptor

Intracellular

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Signal diffuses through membrane

Intracellular

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Ligand binding to receptor activates catalytic domain

Enzyme

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Substance flows along concentration gradient

Ion channel

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Located in cytoplasm of nucleoplasm

Intracellular

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Voltage gated potassium channel

Ion channel

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Insulin receptor

Enzyme linked

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Channel opens or closes

ion channels

Ion channel, GPCR, Enzyme-linked, or Intracellular????? Activates or inhibits an intracellular enzyme

GPCR

Which is NOT a second messenger? a. calcium b. cyclic adenosine monophosphate c. inositol triphosphate d. glutamate

Name the signaling sequence of GPCRs:

1st messenger (ligand) --> GPCR --> Effector --> 2nd messenger --> cellular response

What 3 subunits are. inteh G protein component of GPCR?

alpha, beta, gamma

What activates. theG protein?

The ligand-receptor interaction

What is the function of an effector?

To activate or inhibit second messengers

The intracellular response to second messengers is ___ specific.

Tissue

Name 5 2nd messengers.

1. cAMP 2. cGMP 3. Inositol triphosphate (IP3) 4. Diacylgylcerol (DAG) 5. Calcium Ion (CA2+)

An example. of an endogenous ligand is a ____ or _____.

NT or hormone

A _____ binds to the GPCR.

Ligand

Where does the receptor portion of the GPRC lie?

Outside the cell membrane

Where does the G protein reside?

Inside the cell membrane

What types of G-proteins turn on effectors?

Gs and Gq (these are stimulatory)

What types of G-proteins turn off an effectors?

What activates. a G-protein?

The ligand-receptor interaction

What happens when the G-protein is activated?

The alpha subunit dissociates from the beta and gamma subunits

When does the alpha subunit rejoin the beta and gamma subunits of a G-protein?

When the ligand unbinds from the receptor

What is the purpose of the effector of GPCR?

To produce or activate the 2nd messenger

Enzymatic effectors (that activate/produce the 2nd messenger) include _____ and _______.

adenylate cyclase and phospholipase C

Ion channel effectors (that activate the 2nd messenger) include _____ and ________, at the _____.

GABA-a receptors and M2 receptors. at the SA node

What process allows a single molecule to initiate a process that activates a large number of physiologic changes - each step progressively increasing the magnitude of response? What system allows for this process?

Signal amplification; Second messenger system

The second messenger modulates a network of enzymatic activity, including ____ and ____.

phosphatases and protein kinases

Which component of the GPCR signaling sequence allows for amplification?

second messenger

Stimulation of which receptors increases phospholipase C activity? (select 2) a. Alpha 1 b. vasopressin 1 c. beta-1 d. muscarinic 2

A and B

Gs alpha subunits stimulate what?

adenylate cyclase

What does Gs alpha stimulation promote?

Increased cAMP levels

Gi alpha subunits inhibit what?

Adenylate cyclase

What does Gi inhibition result in?

decreased cAMP levels

Gq alpha subunits activate what? And what does this cause?

Phospholipase C; increased IP3, DAG, and Ca2+

Gq --> Increased ________ effector

Phospholipase C

Gi --> Decreased ________ effector

Adenylate Cyclase

Gs --> Increased ________ effector

Adenylate Cyclase

Gs - second messenger??

increased cAMP

Gi - second messenger??

Decreased cAMP

Gq - second messenger??

Increased IP3, DAG, Ca2+

What is the signal transduction of Alpha 1? (Gq, Gi, or Gs??)

What is the signal transduction of Alpha 2? (Gq, Gi, or Gs??)

What is the signal transduction of Beta 1? (Gq, Gi, or Gs??)

What is the signal transduction of Beta 2? (Gq, Gi, or Gs??)

What is the signal transduction of Beta 3? (Gq, Gi, or Gs??)

What is the signal transduction of Nicotinic Receptors?

Ion channels

What is the signal transduction of M1? (Gq, Gi, or Gs??)

Gq (1,3,5 are all Gq)

What is the signal transduction of M3? (Gq, Gi, or Gs??)

Gq (1,3,5 are all Gq)

What is the signal transduction of M5? (Gq, Gi, or Gs??)

Gq (1,3,5 are all Gq)

What is the signal transduction of M2? (Gq, Gi, or Gs??)

Gi (2, 4 are Gi)

What is the signal transduction of M4? (Gq, Gi, or Gs??)

Gi (2 & 4 are Gi)

What is the signal transduction of Dopamine 1 (postsynaptic)? (Gq, Gi, or Gs??)

What is the signal transduction of Dopamine 2 (presynaptic)? (Gq, Gi, or Gs??)

What is the signal transduction of Vasopressin 1 (vasculature)? (Gq, Gi, or Gs??)

What is the signal transduction of Vasopressin 2 (renal tubules)? (Gq, Gi, or Gs??)

What is the signal transduction of Histamine 1? (Gq, Gi, or Gs??)

What is the signal transduction of Histamine 2? (Gq, Gi, or Gs??)

Match each receptor with its physiologic action? A2 M3 B2 B1 Increased automaticity Coronary vasoconstriction Skeletal muscle vasodilation Bronchoconstriction

Increased automaticity - B1 Coronary vasoconstriction - A2 Skeletal muscle vasodilation - B2 Bronchoconstriction - M3

What does parasympathetic nervous stimulation of M2 receptors cause?

Decreased rate, contraction, and conduction velocity

______ nervous system of B1 receptors. atthe heart causes increased rate, contraction, and conduction velocity.

Sympathetic

Do arteries and veins receive PNS input?

Arteries and veins receive no PNS input, in general. What are the excpetions?

Coronary vessels (vasodilation) and cerebral vessels (receptor-specific vasodilation or vasoconstriction)

SNS stimulation of most arterial vessels causes ______ via what receptors?

vasoconstriction; A1

SNS activation of ___ receptors on veins produces venoconstriction.

SNS stimulation of B2 receptors on most arterial vessels produces what?

vasodilation

What is the PNS effect upon airway smooth muscle and through what receptor?

Contraction of airway smooth muscle; M3

SNS activity produces ____ of airway smooth muscle

relaxation (b2 receptors)

SNS: Effector - Heart Receptor - ______

SNS: Effector - Lungs Receptor - ______

SNS: Effector - GI Tract Receptor - ______

SNS: Effector - Glands Receptor - ______

SNS: Effector - Urinary Tract Receptor - ______

A1, B2

SNS: Effector - Skin Receptor - ______

SNS: Effector - Skeletal Muscle Receptor - ______

SNS: Effector - Pupils Receptor - ______

SNS: Effector - Heart Receptor - B1 Effect - ________

Positive inotropic, chronotropic, and dromotropic effect

SNS: Effector - Lungs Receptor - B2 Effect - ________

Bronchodilation

SNS: Effector - GI Tract Receptor - A1 Effect - ________

Vasoconstriction; Sphincter contraction

SNS: Effector - Glands Receptor - A1 Effect - ________

Increased sweating Decreased pancreatic activity

SNS: Effector - Urinary Tract Receptor - A1, B2 Effect - ________

Bladder sphincter contraction Increased renin secretion

SNS: Effector - Skin Receptor - A1 Effect - ________

Vasoconstriction

SNS: Effector - Skeletal Muscle Receptor - B2 Effect - ________

Vasodilation

SNS: Effector - Pupils Receptor - A1 Effect - ________

Dilation

PNS: Effector - Heart Receptor - ______

PNS: Effector - Lungs Receptor - ______

PNS: Effector - GI Tract Receptor - ______

PNS: Effector - Glands Receptor - ______

M1, M3

PNS: Effector - Urinary Tract Receptor - ______

PNS: Effector - Pupils Receptor - ______

PNS: Effector - Heart Receptor - M2 Effect - ______

Negative inotropic, chronotropic, and dromotropic effect

PNS: Effector - Lungs Receptor - M3 Effect - ______

Bronchconstriction Increased galnd secretion

PNS: Effector - GI Tract Receptor - M3 Effect - ______

Increased motility Sphincter relaxation Increased gland secretion

PNS: Effector - Glands Receptor - M1, M3 Effect - ______

Increased salivation Increased lacrimation Increased pancreatic activity

PNS: Effector - Urinary Tract Receptor - M3 Effect - ______

Bladder sphincter relaxation

PNS: Effector - Pupils Receptor - M3 Effect - ______

Constriction