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

Lecture 19 (exam 3) Flashcards

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
Q

cAMP Is the Intracellular Messenger in the Adenylyl Cyclase Cascade

A

Muscle:
- hormone: Adrenaline (epinephrine) - response: glycogen breakdown

Liver:
- hormone: glucagon
- response: glycogen breakdown

Fat:
- hormone: Adrenaline, ACTH, glucagon, TSH
- receptor: triglyceride breakdown

26
Q

cAMP Is the Allosteric….

A

Activator of Protein Kinase A

27
Q

Protein Kinase A

A

PKA = cAMP-dependent protein kinase

PKA is a serine/threonine protein kinase

28
Q

In the absence of cAMP (PKA)

A

the C (catalytic) subunits are bound to R (regulatory) subunits, which inhibits the catalytic activity

29
Q

A-kinase anchoring proteins (AKAPs)

A

bind to the R subunit to localize PKA to specific subcellular sites (ex. nuclear envelope, plasma membrane, cytoskeleton)

30
Q

PKA is ___ within the cell by binding to ‘Anchoring’ Proteins

A

“localized”

different cells express different PKA anchoring proteins, allowing cell-specific effects of cAMP to occur and even ligand specific effects

Ex. AKAPs

31
Q

The Adenylyl Cyclase Cascade Can Trigger Changes in….

A

Transcription as well as in
Enzyme Activity

  • Activated Gsa activates adenylyl cyclase.
32
Q

CREB

A

cAMP response element binding protein

is a transcription factor

33
Q

CREs

A

cAMP response elements

CREB binds to CREs in target genes such as PEPCK, which regulates gluconeogenesis

34
Q

PEPCK

A

phosphoeonolpyruvate carboxykinase

regulates gluconeogenesis

35
Q

Glucagon Signaling as an Example of an…

A

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
Q

Glucagon Signaling Activates

A

PKA, Leading to Changes in Enzyme Activity and Transcription

Activate Glycogen phosphorylase kinase —> increased glycogenolysis

activate CREB (transcription activator) —> increased gluconeogenesis

37
Q

The Biological Effects of the Ligand Can be Mimicked by Agents That Increase cAMP

A
  • Cholera toxin
  • Plasma membrane permeable derivatives of cAMP
  • cAMP phosphodiesterase (PDE) inhibitors
    (caffeine, theophylline in tea, isobutyl methyl xanthine)
38
Q

Gi ‘inhibits’ adenylyl cyclase

A

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
Q

Both Cholera Toxin and Pertussis Toxin Cause Disease by

A

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
Q

Cholera toxin

A

ADP-ribosylation of Gsa.

41
Q

ADP-ribosylation

A

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
Q

pertussis toxin

A

ADP-ribosylation of
Gia

43
Q

Phosphoinositide (PI) or Inositol Phospholipid (IP) cascade is analogous to…..

A

the adenylyl cyclase cascade

44
Q

Some Physiological Effects Regulated by the Phosphoinositide Pathway

A

LIver: vasopressin, glucagon
Smooth muscle/pancrease: Acetylcholine
Blood platelets: Thrombin

45
Q

Phospholipases

A

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
Q

DAG

A

helps activate some PKC (protein kinase C) family members

DAG is the precursor for arachidonic acid and eicosanoids such as prostaglandins (PGs)

47
Q

PG-Es

A

E series of prostaglandins regulate many important functions such as pain, vasodilation, suppression of gastric acid release, platelet activation, uterine contraction, inflammation

48
Q

Arachidonic acid

A

20 Carbons

a signaling molecule that can be converted to eicosanoids

49
Q

Roles of Calcium in signaling

A
  • 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
Q

EF hand

A

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
Q

Calmodulin (CaM)

A

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
Q
  • GPCRs are a huge family (hundreds in humans) of…
A

7-transmembrane receptors

53
Q

GPCRs bind ligands that range from…

A

large proteins to light waves

54
Q

GPCRs are rapidly inactivated by _____ and kept inactive by_____.

A

GRKs, arrestins

55
Q

Cholera toxin and pertussis toxin cause disease by

A

disrupting signaling through the adenylyl cyclase pathway by ADP-ribosylating Gs and Gi, respectively

56
Q

Some GPCRs activate a trimeric G protein known as

A

Gq.

Gqα activates
phospholipase C-b (PLC-b).

57
Q

IP3 binds to

A

IP3-gated Ca2+ channels (IP3 receptors) in the endoplasmic
reticulum outer membrane, releasing Ca2+ into the cytoplasm

58
Q

DAG modulates____ and is a precursor for___

A

PKC, arachidonic acid

59
Q

Eicosanoids

A

are lipid signaling molecules such as prostaglandins (PGs) that participate in pain and inflammatory responses.

60
Q

Ca2+ allosterically regulates

A

many proteins, most importantly, protein kinase C (PKC) and calmodulin (CaM).

61
Q

IP3

A

inositol triphosphate

Biochem II Self Study (10 decks)

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