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Biochem II Self Study > Lecture 19 (exam 3) > Flashcards

Lecture 19 (exam 3) Flashcards

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1
Q

GPCRs

A

are named because receptor activation by ligand binding trigger activation of a trimeric G protein (3 subunits),

‘G’ protein because it binds GDP and GTP guanine nucleotides

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2
Q

in mammals

A

thousands of genes encode GPCRs, including >100s that respond to different odorants

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3
Q

Therapeutic drugs aimed at specific GPCRs…

A

are among the most effective and commonly-used pharmaceuticals (asthma, high blood pressure, pain relief, etc.)

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4
Q

The GPCR membrane complex

A

Receptors, G protein, Effectors

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5
Q

Receptors

A

sensory, adrenergic, neutrotransmitters, small molecules (prostaglandins, nucleotides), protein hormones

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6
Q

G protein

A

~21 alpha subunits
~ 6 beta subunits
~ 12 gamma-subunits

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7
Q

Effectors

A

Adenylyl cyclase
phospholipases Cbeta and Cgamma
K+ and Ca2+ channels
cGMP phosphodiesterase

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8
Q

Common ligands

A

Acetylcholine, Epinephrine, Glucagon

Light, taste, olfactory

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9
Q

Two major types of G proteins

A

monomeric (small) or heterotrimeric

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10
Q

alpha subunit

A

is a GTPase

has 2 domains:
- Ras domain
- AH (alpha-helical) domain

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11
Q

Ras domain

A

is similar to other GTPases and forms one face of the binding pocket

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12
Q

Alpha helical domain (AH)

A

forms the other side of the guanine nucleotide binding pocket

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13
Q

Gt (transducin) - likely not on exam

A

Activates cyclic GMP phosphodiesterase in vertebrate rod photoreceptors

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14
Q

Gs (G protein)

A

Active subunits: Alpha

Function: activates adenylyl cyclase

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15
Q

Gi (G protein)

A

Active subunits: Alpha, Beta-Gamma

Function: Inhibits adenylyl cyclase, Activates K+ channels

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16
Q

Gq (G protein)

A

Active subunits: Alpha

Function: Activates Phospholipase C-Beta

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17
Q

How does ligand binding to receptor activate G proteins?

A

Ex. Rhodopsin
the thought is that ligand binding to other GPCRs causes a similar conformation change that enables G protein binding and activation

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18
Q

Rhodopsin

A

the GPCR photoreceptor utilizes the cofactor 11-cis-retinal to detect a photon of light.

Retinol isomerization causes an altered arrangement of the intracellular loops of the GPCR so that the G protein transducin (GT) can bind and be activated.

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19
Q

The βγ Subunits of Trimeric G-Proteins Can Also Function as….

A

intracellular signal transducers

Ex.
the effector is a K+ channel. The G-βγ opens the K+ channel

at the same time, the Gialpha component can inhibit adenylyl cyclase

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20
Q

GPCR receptor kinase (GRK)

A

once a ligand binds to a GPCR, it stimulates a GRK, which phosphorylates the receptor

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21
Q

arrestin

A

a scaffold protein that blocks the interaction of the receptor with G proteins and thus stops signaling

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22
Q

β-ARK

A

β-adrenergic receptor kinase

os the most famous GRK because it inactivates receptors coupled to Gα, most notably the adrenergic receptors

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23
Q

GPCRs Are Desensitized by Sequential Mechanisms

A
  1. Receptor inactivation by phosphorylation by GRK
  2. Binding of arrestin to the phosphorylated receptor
  3. Receptor sequestration or 4. down-regulation if the signal remains high for very long
  4. Inactivation of a downstream signaling molecule
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24
Q

cAMP Is the Intracellular Messenger in the Adenylyl Cyclase Cascade

A

Some GCPRs activate Gs
- Gs ‘stimulates’ and activates the adenylyl cyclase (AC) enzyme
- AC synthesizes cAMP from ATP in a cyclization reaction that is fast
- cAMP is very unable as it is hydrolyzed by specific phosphodiesterase (PDEs) to form 5’-AMP

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25
cAMP Is the Intracellular Messenger in the Adenylyl Cyclase Cascade
Muscle: - hormone: Adrenaline (epinephrine) - response: glycogen breakdown Liver: - hormone: glucagon - response: glycogen breakdown Fat: - hormone: Adrenaline, ACTH, glucagon, TSH - receptor: triglyceride breakdown
26
cAMP Is the Allosteric....
Activator of Protein Kinase A
27
Protein Kinase A
PKA = cAMP-dependent protein kinase PKA is a serine/threonine protein kinase
28
In the absence of cAMP (PKA)
the C (catalytic) subunits are bound to R (regulatory) subunits, which inhibits the catalytic activity
29
A-kinase anchoring proteins (AKAPs)
bind to the R subunit to localize PKA to specific subcellular sites (ex. nuclear envelope, plasma membrane, cytoskeleton)
30
PKA is ___ within the cell by binding to 'Anchoring' Proteins
"localized" different cells express different PKA anchoring proteins, allowing cell-specific effects of cAMP to occur and even ligand specific effects Ex. AKAPs
31
The Adenylyl Cyclase Cascade Can Trigger Changes in....
Transcription as well as in Enzyme Activity - Activated Gsa activates adenylyl cyclase.
32
CREB
cAMP response element binding protein is a transcription factor
33
CREs
cAMP response elements CREB binds to CREs in target genes such as PEPCK, which regulates gluconeogenesis
34
PEPCK
phosphoeonolpyruvate carboxykinase regulates gluconeogenesis
35
Glucagon Signaling as an Example of an...
Adenylyl Cyclase Cascade Glucagon is a polypeptide hormone produced in a signaling cell (the α cell in the endocrine pancreas) that is secreted in response to low blood glucose levels (stimulus).
36
Glucagon Signaling Activates
PKA, Leading to Changes in Enzyme Activity and Transcription Activate Glycogen phosphorylase kinase ---> increased glycogenolysis activate CREB (transcription activator) ---> increased gluconeogenesis
37
The Biological Effects of the Ligand Can be Mimicked by Agents That Increase cAMP
- Cholera toxin - Plasma membrane permeable derivatives of cAMP - cAMP phosphodiesterase (PDE) inhibitors (caffeine, theophylline in tea, isobutyl methyl xanthine)
38
Gi 'inhibits' adenylyl cyclase
Adenylyl cyclase always has some basal activity. * Giα inhibits that basal cyclase activity in response to ligand binding to its receptor. * Gsα increases cAMP levels over the normal basal levels.
39
Both Cholera Toxin and Pertussis Toxin Cause Disease by
inappropriately increasing cAMP levels ADP-ribosylation of Gsa inhibits its GTPase activity, meaning that Gsa is permanently in its GTP-bound state and is thus active. ADP-ribosylation of Gi prevents it from interacting with its ligand-bound receptors, so Gi remains in the GDP-bound state and is thus permanently inactive.
40
Cholera toxin
ADP-ribosylation of Gsa.
41
ADP-ribosylation
ADP- ribosylation of Gs a inactivates its GTPase activity, making Gs a permanently active The ADP-ribosylation of Gai blocks its association with the receptor and thus dissociation from bg so the basal activity of adenylyl cyclase is not inhibited and too much cAMP is made.
42
pertussis toxin
ADP-ribosylation of Gia
43
Phosphoinositide (PI) or Inositol Phospholipid (IP) cascade is analogous to.....
the adenylyl cyclase cascade
44
Some Physiological Effects Regulated by the Phosphoinositide Pathway
LIver: vasopressin, glucagon Smooth muscle/pancrease: Acetylcholine Blood platelets: Thrombin
45
Phospholipases
are a family of enzymes that hydrolyze membrane phospholipids at different positions in the molecule Phospholipases of the C subgroup cleave the phosphodiester bond between the glycerol backbone and the phosphate head group.
46
DAG
helps activate some PKC (protein kinase C) family members DAG is the precursor for arachidonic acid and eicosanoids such as prostaglandins (PGs)
47
PG-Es
E series of prostaglandins regulate many important functions such as pain, vasodilation, suppression of gastric acid release, platelet activation, uterine contraction, inflammation
48
Arachidonic acid
20 Carbons a signaling molecule that can be converted to eicosanoids
49
Roles of Calcium in signaling
- Ca2+ is a ubiquitous second messenger - Cytoplasmic Ca2+ is kept low (<0.2 μM, ~10-7 M) even in the face of high extracellular Ca2+ (2 mM, ~10-3 M) by ion pumps so that it doesn’t form a salt with the cytoplasmic phosphate. * External stimuli can induce a transient increase in cytoplasmic Ca2+ by opening ion channels in the plasma membrane or endoplasmic reticulum. * Ca2+ is key to causing the release of secretory vesicles containing various hormones/ligands. * Ca2+ is also key to modulating the activity of various enzymes
50
EF hand
domains bind Ca2+ "looks like the right hand, palm facing you, and last three digits closed. Pointer finger is pointed up and thumb is pointed out"
51
Calmodulin (CaM)
is a major mediator of Ca2+ signaling - Affinity of EF hand domains in CaM for Ca2+ which is perfect for sensing concentrations just above the resting state - When CaM has at least 2 Ca2+ bound, it can change conformation in an almost switch-like manner
52
* GPCRs are a huge family (hundreds in humans) of...
7-transmembrane receptors
53
GPCRs bind ligands that range from...
large proteins to light waves
54
GPCRs are rapidly inactivated by _____ and kept inactive by_____.
GRKs, arrestins
55
Cholera toxin and pertussis toxin cause disease by
disrupting signaling through the adenylyl cyclase pathway by ADP-ribosylating Gs and Gi, respectively
56
Some GPCRs activate a trimeric G protein known as
Gq. Gqα activates phospholipase C-b (PLC-b).
57
IP3 binds to
IP3-gated Ca2+ channels (IP3 receptors) in the endoplasmic reticulum outer membrane, releasing Ca2+ into the cytoplasm
58
DAG modulates____ and is a precursor for___
PKC, arachidonic acid
59
Eicosanoids
are lipid signaling molecules such as prostaglandins (PGs) that participate in pain and inflammatory responses.
60
Ca2+ allosterically regulates
many proteins, most importantly, protein kinase C (PKC) and calmodulin (CaM).
61
IP3
inositol triphosphate

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