Exam 1 Flashcards
(180 cards)
1
Q
enzymes which place phosphates on other molecules
A
kinases
2
Q
enzymes which remove phosphates from molecules
A
phosphatases
3
Q
enzymes that place acetyl groups on lysines
A
acetyltransferases
4
Q
enzymes which remove acetyl groups
A
deacetylase
5
Q
ubiquitin
A
molecule that when attached to a protein, marks it for degradation
6
Q
ubiquitin ligase
A
enzyme complex that places ubiquitin onto a specific lysine residue on a protein
7
Q
how is ubiquitin arranged?
A
as a chain
8
Q
what is proteasome
A
multi-subunit protein complex (1% of total protein) that uses ATP to provide energy to unfold & digest protein into smaller peptide molecules
9
Q
epigenetics
A
changes in gene expression caused by certain pairs of DNA or RNA to be turned on or turned off by chemical reactions
10
Q
how is cell type determined?
A
- what regions of chromatin are open
2. what transcription factors are active
11
Q
What are the functions of the cell membranes
A
- defines the cell
- separates compartments
- controls movement of molecules
- generation of gradients
- scaffold for assembling large molecular complexes
- resource for materials
12
Q
What is important about cell compartment separation by membranes?
A
allows specialized chemical reactions to proceed
allows diverse chemical reactions to occur in close proximity
13
Q
How does a cell membrane control movement of molecules?
A
- uses specialized pumps & channels that span the membrane to get nutrients and eliminate waste
- uses receptors to get and give information
14
Q
what kinds of gradients does a cell membrane generate?
A
voltage gradients (ions) in nerve cells (to power electrical signaling) concentration gradients (to drive pumps)
15
Q
what are some examples of molecular complexes that are assembled using membrane scaffolding?
A
ATP in mitochondria
photoreceptors (detecting light)
signal transduction events
16
Q
What is the structure of a phospholipid?
A
fatty acid chains (acyl groups) (2) attached to glycerol (bridge) attached to polar head group
amphipathic
17
Q
What kind of group is a fatty acid
A
acyl group
18
Q
How do fatty acids hide from water?
A
create a micelle or a bilayer (head groups always facing out towards water)
form spontaneously
make a hydrophobic barrier that prevents charged molecules from crossing from one side to the other
19
Q
what are the properties of a phospholipid bilayer?
A
- spontaneous formation in an aqueous environ. (membranes fold & seal to avoid edges)
- forces create barriers to movement (Van der Waals forces in fatty acid & electrostatic forces in the polar head groups & water)
- membranes are 2 dimensional solutions (lipids diffuse rapidly w/in 1 layer but can’t spontaneously flip to the other layer.
20
Q
what are saturated & unsaturated fatty acids?
A
saturated - all possible hydrogens are bonded to carbons
unsaturated, some carbons have double bonds
21
Q
what do saturated FAs do to membrane structure
A
interact tightly w/each other
maximum van der waals interactions
stiffer membrane
22
Q
what do unsaturated FA do to membrane structure?
A
have a kink where carbon double bond is - blocks some of the van der wall interactions. mechanism by which melting point decreases - affects fluidity - makes membrane more fluid
23
Q
what are other components of a cell membrane besides phospholipids?
A
sphingolipids
cholesterol
24
Q
what is the structure of a sphingolipid?
A
uses sphingosine as the backbone instead of glycerol
25
what is the structure of cholesterol?
amphipathic ring structure
26
what is the 2nd largest class of membrane lipids?
sphingolipids
27
what is a ceramide?
sphingosine with one fatty acid - formed when acyl group (O=C-R C bonds to the N on NH3+) from CoA transfers onto the amine of sphingosine
28
why is ceramide important?
parent compound for all sphingolipids
29
What is a ganglioside?
a sphingolipid - like a phospholipid except it has a sugar on it instead of a head group - the sugar chain contains some information
30
what is the simplest ganglioside?
cerebroside - contains either a glucose or a galactose
31
what do most gangliosides terminate in?
sialic acids (acidic sugars) - negatively charged
32
why are the surface of most cells negatively charged?
b/c of the gangliosides that terminate in sialic acids which are negatively charged
33
how are gangliosides distributed in the cell membrane?
NOT uniformly - appear to associate w/signaling proteins
34
what is a lipid raft?
a signaling platform in the membrane ocean
35
what do gangliosides do w/lipid raft?
appear to be vital for structure of raft
36
where is the highest concentration of gangliosides found?
brain - where they are 6% of lipids
37
what happens to ganglioside population during development?
can change - also can change during tumor progression - potential to identify tumor cells by gangliosides they express & use that info to make specific targets in treatment of tumors
38
what determines blood groups?
gangliosides - the carbohydrate moieties on sphingolipids
all 3 blood types of 2 of the same sugars, type A and type B have a specific type of 3rd sugar and type O has neither of those two sugars
39
moiety
part of a molecule
40
What are some ganglioside diseases?
Tay-Sachs disease
Guillain-Barre syndrome
Alzheimer's disease
41
what is the nature of ganglioside diseases?
there is a disruption in ganglioside breakdown
42
describe Tay-Sachs disease
loss of ability to remove the terminal N-acetylgalactosamine residue (genetic disease where enzyme is screwed up so that residue can't be removed - GM2 processing defect) - weakness, retardation, death by 3 y.o. neurons get swollen w/lipid-filled lysosomes and undergo apoptosis or autophagy : processing defect - disease of the brain - something about the sugar isn't processed right
43
describe Guillain-Barre syndrome
acute inflammatory disease triggered by strong infection affecting peripheral nervous system - autoantibodies produced against gangliosides damage axons - another processing defect: auto-immune disease - against gangliosides - inflammatory disease triggered by infection
44
How is Alzheimer's disease related to gangliosides?
too much ganglioside GM1 contributes to aggregation of amyloid beta-protein deposits - gangliosides contribute to aggregation of amyloids - amyloid plaque
45
what does cholesterol do to cell membrane?
maintains cell membrane integrity and membrane fluidity
46
how physically is cholesterol inserted into the membrane?
hydroxyl group on end of steroid ring points out and rings & tail point into the membrane
47
How does cholesterol maintain cell membrane integrity?
rings interact w/neighboring fatty acid
cholesterol (ring part) is rigid so it adds firmness to membrane
decreases permeability of membrane to small water soluble molecules
48
how does cholesterol maintain membrane fluidity?
breaks up interactions between fatty acids - so keeps membrane from extreme states - not too fluid, not too stiff - just right, goldilocks
49
where is cholesterol found in the membrane?
in lipid rafts - not distributed easily - some clustering
50
what are lipid rafts composed of?
primarily sphingolipids (gangliosides) and cholesterol
51
where are lipid rafts found?
primarily in outer exoplasmic leaflet of cell membranes - connected to phospholipids & cholesterol w/in inner cytoplasmic leaflet
52
what else likes to be in the lipid raft environment?
certain transmembrane receptors - properties of the raft seem important in the modulation of the activity of these receptors
53
what do lipid rafts have to do with Alzheimer's Disease?
play role in the pattern of cleavage in amyloid proteins
amyloid beta-peptide (Abeta) is derived from cleavage of a larger protein - major contributor to amyloid plaques that kill neurons. Cholesterol levels are important for Abeta formation. the epsilon4 allele of the apoE gene (carrier that delivers cholesterol within the CNS) is major risk factor for alzheimers - genetic evidence links cholesterol level to alzheimers
54
what do many of the functions of the membrane involve?
proteins that actually perform that function
55
what is an example of a membrane function that doesn't require protein?
myelin membrane - insulate electrical signals passed by axons - protein content of myelin is less than 25% of membrane
56
what is an example of a function that requires lots of proteins?
production of ATP in mitochondrial membrane - protein content of internal mitochondrial membrane is approx 75% (just enough phospholipids to hold the thing together as a membrane)
57
what is the protein content of a typical plasma membrane?
approx 50% protein
58
what are the 8 ways proteins associate with the membrane?
1. single transmembrane alpha helix
2. multiple alpha helices span the membrane
3. rolled up beta sheet (beta barrel) spans the membrane
4. alpha helix only spans one leaflet of the membrane
5. lipid is covalently attached to the protein & inserts into the inner leaflet
6. membrane associated protein interacts via non-covalent binding to an oligosaccharide
7. intracellular membrane associated protein interacts w/an integral membrane protein
8. extracellular membrane associated protein interacts w/an integral membrane protein
59
What are characteristics of a membrane spanning alpha helix protein?
amino acids of protein are in lipid env.
Most must be uncharged for it to be energetically favorable
peptide bonds are polar, so they have to form H-bonds
alpha helix maxes h-bonds so outer surface is uncharged to interact w/hydrophobic tails
60
How does information transfer using a membrane spanning alpha helix?
ligand bonds to outside, helix can't change much due to h-bonds, but can rotate, twist or move up & down - enough to create the signal that moves from outside to inside
61
What is a tight junction?
- created by membrane proteins to create a diffusion barrier
- i.e. epithelial cells w/apical membrane that has tight junctions b/t cells so that proteins can't diffuse past the tight junctions
- separates the membranes into domains
62
what do tight junctions do?
limit movement of proteins - creates domains in the membrane
63
What determines where membrane proteins go?
endoplasmic reticulum - sorts the membrane proteins & sends them to their destinations
64
do cells in tissues have sides?
yes, apical and basal
| basal side faces the basement membrane,
65
what happens in retinal pigment epithelia?
have tight junctions: apical side involved in recycling components - absorbs nutrients from blood on basal side - drugs can be developed to target specific tissue regions by taking advantage of differences b/t apical and basal sides
66
What are some ways the mobility of proteins can be restricted?
1. self-assembly into aggregates
2. tethering by an extracellular protein (i.e. t-cells and b-cells get tethered by antigens)
3. tethering by an intracellular protein
4. cell-cell interactions (i.e. t-cells & antigen presenting cells)
67
Why is protein mobility restricted?
to achieve a purpose
often to construct a multi protein complex to perform a physiological task - like having many receptors signal together in one spot on the cell
68
where are protein lattices?
both inside & outside cells
intracellular lattice is cytoskeleton
intercellular lattice is basement membrane or extracellular matrix
69
what are cell membranes connected to?
w/in the cell - cytoskeleton
| w/out the cell - extracellular matrix
70
what are the types of signaling?
direct cell-cell signaling
endocrine signaling - national news
paracrine signaling - neighborhood gossip
autocrine signaling - leaving yourself a note
71
what are some examples of cell to cell signaling?
immune system, integrins, cadherins
| specificity is that cells have to be next to each other.
72
what are examples of endocrine signaling?
hormones - signal goes everywhere but only certain cells have receptors to receive the signal
specificity is the receptor
73
What are some examples of paracrine signaling?
eicosanoids, neurotransmitters, prostaglandins, leukotrienes
sometimes there's a barrier to keep them local, many are proteins (enzymes) that are chemically unstable & can diffuse just a small ways before breaking down
74
What is an example of autocrine signaling?
T-cell that is recognizing an antigen - has to stimulate itself to rapidly divide
cancer cells
75
How do immune cells signal?
B-cells, T-cells & macrophages - highly mobile, express molecules on their cell surfaces - go places and do things - cell to cell interactions
76
How do tissues use cell-cell signaling?
Interact w/mobile cells like immune cells & new blood vessels - interact w/each other through integrins & other cell adhesion molecules (involved w/keeping tissue together & also w/cell signaling).
77
Where does specificity occur w/endocrine signaling?
at receptor level
cells w/out receptors ignore signal
signal distributed throughout body - perfect way to coordinate distant body parts towards one function
78
where does the regulation occur with endocrine signaling?
at the point of release & at the point point of signal detection (cell could be turned on or turned off - used for a variety of purposes)
79
Where is endocrine signaling used?
many different tissues for many different purposes - i.e. steroid hormones, insulin, and adrenaline
80
Why does the body use paracrine signaling?
To keep a signal more or less localized.
regulation is at level of generating the signal. If molecule is unstable, it will only diffuse a few cell diameters b4 it degrades
81
What tissues use paracrine signaling and for what purposes?
many different tissues, many different purposes. for example, NO is secreted by vascular endothelial cells & acts on vascular smooth muscle to promote relaxation
82
What is synaptic transmission?
specialized form of paracrine signaling. concentration of neurotransmitter is high w/little or no leakage. diffusion from presynaptic terminal to postsynaptic receptor is super fast. allows neighboring cells to carry completely different signaling info. neurotransmitters are held in synaptic vesicles before they go across the synapse to the ligand-gated channels on the receiving side
83
what is a synapse?
specialized structure where a tiny bit of fluid separates the presynaptic cell from the post synaptic cell
84
What does autocrine signaling do?
provides a positive feedback loop, useful for rapidly promoting proliferation, immune response arises from activation of a single t-cell, cancer cells also make sure of this process for rapid division.
85
How are blood sugar levels sensed?
in the beta cells of the islets of langerhans w/in pancreas
86
What causes the release of insulin into the blood stream?
glucose sensors in the beta cells of islets of langerhans in pancreas sense glucose levels. [as an aside: pre-proinsulin is converted to insulin in vesicles derived from the Golgi]. when glucose levels rise, induces transient Ca++ release, promotes fusion of vesicles w/surface of beta cell & release of contents (insulin).
87
What causes release of Histamine?
Histamine is released from Mast cells in response to allergens. Allergens bind to IgE expressed on surface of Mast cell. Binding induces signal transduction cascade that mobilizes Ca++ - promoste vesicular fusion & releases histamine.
88
What is TNFalpha
tumor necrosis factor - important inflammatory signaling protein
89
How is TNFalpha released from cell?
TACE (also a membrane bound protein) is a protease that cleaves TNFalpha (a membrane bound protein and a cytokine) (NOT a quantal release mechanism). Soluble TNF can diffuse to site of action. Soluble AND membrane TNF can activate TNFalpha receptors on neighboring cells.
90
what is a protease
enzyme that breaks down proteins and peptides
91
What happens to the remnant membrane TNF after getting cleaved?
it is recycled
92
What is the point of a drug that can distinguish b/t soluble and membrane bound forms of TNF?
may have fewer side effects
93
What kind of therapy might blockade of TNF signaling be used for?
treatment of rheumatoid arthritis
94
What is continuous release?
signaling molecules that are released as soon as they are made
95
what are some examples of continuous release molecules?
steroid hormones (estrogen, progesterone, testosterone, corticosterone, aldosterone), prostaglandins, cytokines (other than TNFalpha)
96
Where is regulation with continuous release molecules?
at the level of synthesis of the signaling molecule (NOT at the level of release)
97
how might synthesis regulation occur for continuous release signaling molecules?
could be transcriptional (synthesis of mRNA) or translational (synthesis of protein)
98
how are continuous release molecules actually released?
peptides are released via a continuous vesicular exocytosis and small (uncharged) molecules diffuse out of the cell
99
what is the benefit of diffusion for signaling molecule transport?
allows all cells w/in an area to receive the signal. if signal is also unstable & short-lived, this is a good mechanism to keep the signal localized - a strategy for maintaining specificity
100
prostaglandins are an example of what?
signaling molecules that provide local signaling - many spontaneously degrade w/in minutes, some actively degraded by enzymes in lung
- heavily used during inflammation
- used by several organs to regulate blood flow (heart & kidneys)
- used in brain to regulate fever
- also many more processes
101
What is a benefit of local signaling?
allows one molecule to be used for many different physiological purposes (like prostaglandin)
102
What allows creation of concentration gradients?
diffusion
103
what are concentration gradients often used for?
often during development to create specialized cells w/in a tissue - more signal leads to a fundamentally different cell response (different genes are activated) - multiple cell types within one tissue
-also create a direction
104
Of what use is gradient created direction?
-immune cells follow gradients of signal to find infection
-more signals on one side of cell cause cell to extend its cytoskeleton in that direction while retracting cytoskeleton on all other sides
-result is net movement towards the source of the signal
also used in angiogenesis
105
Receptor
a specific protein in either the plasma membrane or interior of a target cell with which a chemical messenger combines to exert its effects
106
Down-regulation
a decrease in the total number of target cell receptors for a given messenger in response to chronic high extracellular concentration of the messenger
107
Up-regulation
an increase in the total number of target cell receptors for a given messenger in response to chronic low extracellular concentration of the messenger
108
Ligand
a compound (small molecule or protein) which binds to a receptor. A ligand can be an endogenous compound or a drug
109
Affinity
The strength with which a chemical messenger binds to its receptor
110
Agonist
a chemical messenger that binds to a receptor and triggers the cell's response; often refers to a drug that mimics an endogenous messenger's action. (activates)
111
Antagonist
a molecule that competes for a receptor with an endogenous chemical messenger. The antagonist binds to the receptor but does not trigger the cell's response (inhibits)
112
Saturation
the degree to which receptors are occupied by a messenger. If all are occupied, the receptors are fully saturated; if half are occupied, saturation is 50%; etc.
113
Specificity
Selectivity; the ability of a receptor to react with a limited number of structurally related types of molecules
114
Competition
The ability of different molecules very similar in structure to combine with the same receptor
115
Receptor binding vs. cellular effect
-effect of a signal on cell is not binary - # of receptors activated can correlate w/strength of cellular effect
116
what is spare receptor theory
a maximal signal can often be elicited when only a small fraction of receptors are activated
117
desenitization
loss of receptor sensitivity
118
priming
increased receptor sensitivity
119
how can receptor strength be modulated?
w/many important receptor systems - cell has ability to either increase the signal strength or decrease the signal strength caused by the occupancy & activation of a receptor
120
what is an intracellular receptor?
lives inside the cell. ligand has to find a way into the cell by itself.
121
what is an example of an intracellular receptor?
steroid hormone receptors:
| examples of steroid hormones: glucocorticoids, mineralocordicoids, estrogens - diffuse across the cell membrane
122
What happens when steroid hormone diffuses across the cell membrane?
binds to steroid hormone receptor to create receptor complex (activates the receptor), that binds to DNA & activates the transcription of new genes or blocks transcription of genes
123
What is an example of an ion channel?
acetylcholine receptors
124
how does the ACh receptor work?
It's an ion channel. ACh binds to it and drives it to the open state. Continued binding of ACh drives receptor into desensitized state (closed), removal of ACh allows receptor to resume resting state. ACh is degraded by cholinesterases.
125
What is the path to activation in the ACh receptor?
made up of lots of alpha helices - rotate & move in specific ways through the membrane to open the gate. Ion channel opens when you go from resting to activated/excited state so ions move through. quickly goes to desensitized state & stuck there until ACh is removed. then goes to resting state
126
what places in your body use nicotinic acetylcholine receptors?
muscles and brain
| so if you make ACh that can't be degraded, you have a poison - patient is paralyzed
127
How does calcium flood the pancreatic beta cell?
Glucose comes in the glucose sensor, goes through the citric acid cycle and metabolized to ATP. Another ion channel has binding site for ATP on the inside of the cell membrane. ATP binds & causes ion channel to close (it's a K+ channel). loss of inward K+ current results in net depolarization of membrane. Voltage sensitive Ca++ channels open & bring Ca++ into the cell. Ca++ promotes vesicle fusion.
128
How do sulfonylurea drugs work?
Target ATP sensitive K+ channels - keep them closed so more insulin is secreted (because voltage sensitive Ca++ channels open in response to depolarization, Ca++ promotes vesicle fusion). One of first drugs given to diabetes patients - induces insulin release by mimicking ATP in pancreatic beta cell.
129
What are gap junctions?
6 membered protein structures (6 connexin molecules forming a hexagonal structure) that span a gap b/t adjacent cells & couple the cytoplasm of both cells
found in the heart & liver
130
how do gap junctions form?
2 channels have to line up from 2 neighboring cells for a functional connection to be made - only then is a gap junction formed
131
How is the opening & closing of gap junctions regulated?
- low intracellular calcium opens the channel
- high calcium closes the channel
- calcium is the ligand and the gap junction is the receptor
- purpose of closing gap junction is to protect the cell (increase in Ca++ is indicative of cellular damage)
132
What can pass through a gap junction?
only ions & metabolites (it's a small pore)
133
How is the gap junction used by the body?
- electrical coupling: heart & smooth muscle can react quickly to changes in electrical stimulation by contracting due to movement of ions through gap junction
- metabolic signaling: liver produces glucose from amino acids when needed (gluneogdnesis). Adrenaline/epinephrine is secreted from nerve terminals to signal this event. As not all liver cells are next to nerve terminals, the signal is propagated through gap junctions to rapidly increase the liver's response to maintain glucose homeostasis
134
What good is gap junction inhibition?
maybe -
gap junctions are source of drug induced liver injury b/c intracellular inflammatory signaling molecules can be spread quickly through tissues via gap junctions
drug induced injury is one of most common reasons drug development is abandoned (tylenol is big offender)
-Patel & colleagues recently shown direct connection b/t gap junctions and drug induced liver injury - mice genetically engineered to be missing a liver gap junction gene are resistant to liver injury - identified a small molecule inhibitor of liver gap junctions & showed it protected against APAP induced liver injury.
135
what is the structure of all g protein coupled receptors?
all have 7 transmembrane domain (serpentine receptor)
136
How does ligand bonding affect g protein coupled receptors
ligand makes hydrogen bonds w/amino acids found on the outside of cell. # & strength of H-bonds determines affinity of ligand for its receptor. position of H-bonding amino acids determines the specificity of the receptor - only some ligands can interact
binding causes relatively stiff alpha helices to slide & rotate against each other
large effect on conformation of intracellular side of the receptor
137
What happens when g protein coupled receptors get activated?
hormone binds to the receptors. There is a shape change. G protein which associates w/receptor when its inactive, releases from receptor (after it is activated) and migrates along membrane to interact w/its target. target is usually an enzyme, depending on the G protein it will either be turned on or turned off.
138
why is a g protein called a g protein?
b/ it binds to GTP
139
How do tyrosine kinase linked receptors work?
activation via dimerization of subunits:
go from 2 subunits w/single alpha helices (contain a kinase activity - puts phosphate covalently onto something), as monomer, kinase has no access to substrates, substrate for each kinase is the other subunit, ligand binds to both so they come together & supply each other with their substrates
phosphorylation alters the charge & so the conformation of the intracellular surface changes, creating a new binding site which recruits further signaling components. ta da!
140
what are the physiological functions of the beta adrenergic receptor?
- increase heart rate
- increase blood pressure
- decrease airway resistance
- increase gluconeogenesis
- increase muscle glycogen breakdown
- fight or flight response
141
How does the beta adrenergic receptor work?
It's a G protein coupled receptor:
G protein is in 3 parts (alpha, beta gamma). before ligand binds to receptor, g protein has GDP bound to the alpha subunit. hormone(norepinephrine) binds to the beta adrenergic receptor, induces conformational change, GDP has lower affinity for binding site, GTP has higher affinity for binding site so kicks out GDP, bound GTP diffuses across membrane & finds adenylyl cyclic and cranks out cAMP.
g protein is an enzyme, but only involved in on-off signal, not the signal itself
142
what health issues can be addressed by manipulating the beta adrenergic receptor pathway?
Heart disease - blocking receptors will decrease blood pressure
Asthma - activating receptors will open the airway (decrease airway resistance)
143
What does g protein do when it's activated?
shuttles to adenylate cyclase & activates enzyme (on switch)
144
What happens to active G protein eventually?
bound GTP is hydrolyzed to GDP & alpha subunit returns to inactive receptor complex
145
How does the enzymatic activity of the G protein affect its signal?
The more active the enzymatic activity of the G protein is, the faster the receptor's signal turns off. Decreased GTPase activity results in a STRONGER signal
146
What do g proteins do?
hydrolyze GTP to GDP
| so when GTP is hydrolyzed to GDP, it then binds on the adrenergic receptor and turns off receptor's signal.
147
what do phosphodiesterases do?
supply the off signal by converting cAMP to AMP
148
How can you increase levels of cAMP?
receptor mediated activation of adenylate cyclase levels
149
How are adenylate cyclase & phophodiesterase activity regulated?
signal transduction events
150
what does cAMP do?
binds to the regulatory subunits of PKA (protein kinase A)
151
what is the structure of inactive PKA?
2 regulatory subunits (each w/2 with empty cAMP sites) and 2 catalytic subunits. substrate-binding sites on catalytic subunits are blocked by auto inhibitory domains of R subunits
152
what happens when cAMP binds to PKA?
binds to regulatory subunits, catalytic subunits fall off & expose substrate binding sites - go off and do their thing -> removal of inhibition (common theme in signal transduction)
153
what does PKA do?
phosphorylates numerous cellular proteins @ serine & threonine residues
154
what does phosphorylation accomplish?
- leads to activation or inhibition of downstream proteins
- leads to cell specific responses
- range of effects include ion channels, transport systems, secretion, metabolism & gene expression
155
What is an important component of signal transduction?
signal amplification
156
Where does signal amplification take place in signal transduction?
between active adenylate cyclase & cAMP, between active protein kinase & phosphorylated enzyme, and between phosphorylated enzyme and products
NOT between messenger-receptor and active adenylate cyclase or b/t cAMP and active protein kinase
activation occurs when we have enzymes
157
what is the receptor/g protein linkage that stimulates glycogen breakdown and smooth muscle relaxation?
epinephrine is stimulus
| beta2 adrenergic receptor, Gs protein, adenylate cyclase effector
158
what is the receptor/g protein linkage that stimulates smooth muscle relaxation?
PGE2 is stimulus (prostaglandin), EP2 is receptor, Gs is G protein, Adenylate cyclase is effector
159
what is the receptor/g protein linkage that stimulates vascular smooth muscle contraction?
norepinephrine is stimulus, alpha 1-adrenergic is the receptor, Gq is the g-protein, phospholipase C is the effector
160
what is the receptor/g protein linkage that stimulates airway smooth muscle contraction?
LTC4 is stimulus, LTC4 receptor is the receptor, Gq is the g protein, phospholipase C is the effector
161
What is the receptor/g protein linkage that slows pacemaker activity in the heart?
Acetylcholine stimulus, muscarinic m2AChR receptor, Gi-bg is g protein (i for inhibitor), K+ channel is the effector
162
what is the receptor/g protein linkage that works on olfaction?
odorants are stimulus, olfactory receptor, G-olf protein, adenylate cyclase is effector
163
what is the receptor/g protein linkage that works for visual excitation?
light is stimulus, rhodopsin is receptor, transducer is the g-protein, cGMP phosphodiesterase is the effector
164
what is the physiological function of the muscarinic acetylcholine receptor?
feed or breed response:
- decreased heart rate & blood pressure
- increased blood flow to gut
- decreased muscle glycogen breakdown and gluconeogenesis
165
what kinds of things to g proteins do in muscarinic acetylcholine receptors (mAchR)?
some g proteins bind to ion channels (-potassium channels: (M current, GIRK channels, -voltage-operated Ca++ channels), some g proteins activate other kinases (MAP kinases, PKC) some g proteins inhibit adenylate cyclase
166
what do muscarinic receptors do to blood pressure?
decrease it via NO (nitric oxide)
167
How is nitric oxide made in the body?
by deamination of arginine via the enzyme NO synthase
NO synthase is activated via G protein coupled event
NO exists as gas dissolved in liquid environment. has very short half-life of 5-10 seconds - just enough time to diffuse to neighboring cell.
168
how do muscarinic receptors activate NO synthase?
receptors of autonomic nervous system
NO rapidly diffuses across to smooth muscle cell
w/in cell, NO binds to its receptor, guanylyl cyclase
gynylyl cyclase converts GTP to cGMP (similar to production of cAMP), promotes relaxation of smooth muscle cell
-nitroglycerine relieves angina by being converted to NO
169
What are some processes that are regulated by calcium binding?
muscle contraction (actin:myosin interactions)
cytoskeletal movement
vesicular fusion with the membrane
modulation of kinase activity
170
what is the most important calcium binding protein?
calmodulin
makes up 1% of ALL proteins in the cell
many chemical signaling events modulated by calcium occur through interactions w/specific proteins
171
what is CaM
calmodulin
consists of 1 polypeptide chain w/4 binding sites for calcium
at least 2 calcium ions must bind before CaM becomes active
when activated - marked conformational change
acts as translator for calcium events
extended when Ca++ isn't present
number of signals regulated by calcium are enormous
172
What is CaM kinase II?
calcium calmodulin kinase II
expressed at high levels in certain synapses
functions as molecular memory switch
when calcium is present, becomes activated
remains active even after calcium signal has decayed by self phosphorylation
ultimately, kinase is turned off by physically removing the phosphates w/a phosphatase
this is an example of using a transient signal to create a long lasting change - a memory event
173
What is an example of a receptor tyrosine kinase?
the EGF receptor (epidermal growth factor receptor)
174
how does the EGF receptor work?
1. EGF binds to receptor & activates kinase activity w/in its intracellular domains
2. kinase domains phosphorylate each other
3. Grb-2/Sos complex recognizes the phosphorylated domain of the EGFR as a binding site & binds (Grb-2/Sos is protein complex)
4. Sos binds to Ras. Ras is held @ surface of plasma membrane by fatty acid chain (farnesyl group) that inserts into the membrane. binding of Sos causes Ras to release a molecule of GDP & bind a molecule of GTP (ras like G protein)
5. activated Ras (GTP bound) activates serene kinase called Raf-1, Raf-1 phosphorylates Mek-1 & activates it, Mek-1 phosphorylates Map kinase and activates it.
6. Map kinase is released to perform multiple functions w/in the cell
the more active the GTPAse, the less strong the signal
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What about Ras?
functions like a g protein, but different structure & doesn't bind to serpentine receptors - all members of the Ras family are tethered to the membrane w/covalently attached lipid group.
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what does Ras do?
lots of things
insulin signaling
involved in process of proliferation: blockage of ras blocks cell proliferation in vitro while activation of ras promotes proliferation
30% of human cancers have activating ras mutations
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how has ras been targeted by drugs?
inhibiting transfer of the lipid (farnesyl group) onto the protein - called farnesyl transferase inhibitors - Ras is still functional but not localized to the membrane
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What is the MAPK signaling cascade?
combination of 3 kinases (evolutionarily conserved motif in signal transduction)
Ras GTPase is the input - activates MAPKKK which phosphorylates MPKK which phosphorylates MAPK (the output), MAPK can phosphorylate many targets w/in cell
one receptor activates many MAPK molecules (amplification)
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why is the 3 kinase cascade useful?
several different MAPKKK, MAPKK & MAPK proteins - many can interact to form different cascades & exist w/in the same cell, so dozens of proteins can form hundreds of different & unique cascades
specificity is maintained by preassembling these units
so you can combine different inputs & outputs using an adaptor (middle) kinase
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What are examples of duration of signal using MAP kinase cascade?
EGF mediated Ras activation peaks at 5 minutes then declines
| Nerve growth factor (NGF) mediated Ras activation remains high for hours - cell leaves the cell cycle & differentiates
