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Pharmacology Midterm (edit) > Lecture 3 Part 2 > Flashcards

Lecture 3 Part 2 Flashcards

1
Q

Gs and other G proteins use a molecular mechanism that involves what?

A

the binding and hydrolysis of GTP

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2
Q

what does GDP and GTP stand for?

A

GDP = guanosine diphosphate
GTP = guanosine triphosphate

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3
Q

when the GPCR (G protein coupled receptor) is NOT ACTIVATED by a ligand, what is it associated with?

A

guanosine diphophate (GDP)

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4
Q

when the GPCR IS activated by a ligand, what happens?

A

GDP is released and GTP enters the nucleotide binding site of the G protein

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5
Q

what happens after the GPCR has been activated by a ligand and GDP has been released and GTP has entered the nucleotide binding site of the G protein?

A

the activated G protein (now bound to GTP) migrates from the receptor and goes to regulate the activity of an EFFECTOR ENZYME or an ION CHANNEL

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6
Q

what are the potential effectors of an activated G protein (one bound to GTP)

A

-an effector enzyme

-an ion channel (E)

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7
Q

as mentioned, an activated G protein can regulate the activity of either an effector enzyme or an ion channel (E)

what stops the signal?

A

the hydrolysis of GTP stops the signal and E active –> E

the G protein is now again bound to GDP and couples back with the receptor to await activation

(1 inorganic phosphate is released from GTP-> GDP)

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8
Q

true or false

when the G protein is bound to GDP, it is said to be in an inactive state

A

true

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9
Q

true or false

once the ligand has activated the G protein to release its GDP and bind to GTP, it doesn’t matter whether or not the receptor ligand is still bound or free

A

TRUE

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10
Q

what is the rate limiting step in the termination of effector activation in the case of GPCRs?

A

the hydrolysis of GTP to GDP

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11
Q

what determines how long the effect produced by a GPCR will last?

A

the rate limiting step – hydrolysis of GTP to GDP

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12
Q

true or false

cGMP is not a second messenger

A

false - it is

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13
Q

true or false

NE (norepinephrine) works via a G-protein coupled receptor

A

true - it’s a cetecholamine

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14
Q

explain how the rate limiting step for the effect of a G protein is not determined by how long the ligand is bound to the receptor

A

a neurotransmitter like norepinephrine may only encounter its receptor for milliseconds.

but, when the Gs protein coupled to the NE receptor binds GTP and is activated, it may remain active for TENS OF SECONDS – enormously amplifying the original signal

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15
Q

which 3 subfamilies of G proteins are most important and usual for drugs?

A

Gs
Gi
Gq

Gs = G stimulatory
Gi = G inhibitory
Gq

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16
Q

name the ligands for Gs

A

beta-adrenergic amines
glucagon
histamine
serotonin
other HORMONES

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17
Q

Further classify Gi subfamily

A

Gi1
Gi2
Gi3

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18
Q

name the ligands for Gi

A

alpha2-adrenergic amines
acetylcholine (muscarinic)
opioids
serotonin
others

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19
Q

name the ligands for Gq

A

acetylcholine (muscarinic)
serotonin (5-HT1C)
many others

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20
Q

state the effector/signaling path for Gs

A

increased adenylyl cyclase activity
increased cAMP and calcium channel activation

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21
Q

state the effector/signaling path for Gi

A

decreased adenylyl cyclase
decreased cAMP
cardiac K+ channels open, decreases heart rate

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22
Q

what are the ligands for Golf

A

odorants

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23
Q

state the effector/signaling path for Golf

A

decreased adenylyl cyclase and decreased cAMP

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24
Q

what are the ligands for Go

A

neurotransmitters in the brain

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25
Q

state the effector/signaling path for Go

A

not clear

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26
Q

State the effector/signaling path of Gq

A

increased cytoplasmic calcium
all 2nd messengers increased
DAG
IP3
phospholipase c activity

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27
Q

what are the ligands for Gt(1-2)

A

photons
rhodopsin - retinal rods
color opsonins - cone cells

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28
Q

state the effector/signaling path of Gt(1-2)

A

increased cGMP phosphodiesterase

decreased cGMP (phototransduction)

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29
Q

some GPCR’s are also called ___________. why?

A

Serpentine receptors bc the receptor polypeptide chain resembles a snake

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30
Q

true or false

“serpentine” receptors are GPCR’s

A

true

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31
Q

serpentine receptors are GPCR’s and are often called….

A

7 transmembrane spanning receptors

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32
Q

explain the structure of serpentine receptors

A

extracellular amino terminus (N) NH2
intracellular carboxy terminus (C) COOH

spans the membrane 7 times

consists of extracellular and intracellular loops

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33
Q

true or false

all GPCR’s are serpentine receptors

A

false - only some

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34
Q

in serpentine receptors, is the amino group extracellular or intracellular?

A

extracellular

carboxy group (COOH) is intracellular

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35
Q

name 2 potential ligands for serpentine receptors.
where does the ligand bind?

A

catecholamines and acetylcholine

binds within the pocket formed by the 7 transmembrane regions

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36
Q

after the ligand binds within the pocket of the serpentine receptor, what happens?

A

there is a conformational change in the receptor.

this is sensed by the loops within the cytoplasm and the G protein gets activated (GDP becomes GTP) and dissociates from the receptor

GTP gets hydrolyzed back to GDP and the G protein-GDP complex is INACTIVE and couples again with the receptor

37
Q

in serpentine GPCR, what may be associated with diminished interaction between the receptor and G protein?

A

the cytoplasmic tail of the GPCR contains SERINE and THREONINE residues.

these serine and threonine residues can be phosphorylated and this phosphorylation may be associated with diminished interaction between receptor and G protein

38
Q

_________ responses to drugs and hormonal agonists often DESENSITIZE with time

A

receptor-mediated responses

39
Q

true or false

desensitization is usually irreversible

A

false - usually reversible

40
Q

define desensitization

A

occurs when even though the receptors are saturated with agonist, the response gradually decreases

41
Q

true or false

many kinds of receptors undergo desensitization

A

true

42
Q

true or false

although many kinds of receptors undergo desensitization, the mechanism is not clear in most cases

A

TRUE - like the nicotinic acetylcholine receptor

the beta-adrenoceptor desensitization mechanism, however, has been worked out in some detail

43
Q

explain the mechanism of beta-adrenoceptor desensitization

A

when the ligand binds, Gs-GTP and bARK (b-adrenergic receptor kinase) is activated.

bARK PHOSPHORYLATES the cytoplasmic tail on the serine and threonine residues. this increases the affinity of b-arrestin to bind

b-arrestin (protein) then binds to the cytoplasmic tail. this results in a diminished ability for the receptor to interact with the G protein. THUS, THE RESPONSE TO THE AGONIST IS REDUCED

44
Q

In the desensitization mechanism of the b-adrenoceptor, what happens when the agonist is removed?

A

-phosphatases cleave the phosphates from the cytoplasmic tail (originally placed there by bARK)

-bARK activity is decreased (stops phosphorylating the tail of the receptor)

-receptor has now “reset” itself and is now ready to fully respond to the agonist

45
Q

in the desensitization mechanism for b-adrenoceptor, why is it that even though the ligand (agonist) is bound, the response will be decreased

A

the G protein-GDP can’t be activated because it can’t bind to the 3rd intracellular loop of the receptor – it is occupied by b-arrestin

46
Q

true or false

once the ligand dissociates from the receptor, bARK is inactivated

A

true

47
Q

when agonist is NOT bound to the receptor, explain what is happening to the beta-adrenoceptor

A

the inorganic phophates are released, beta-arrestin dissociates from the cytoplasmic tail, and the G protein-GDP complex can now couple with the receptor

the receptor has now “reset” itself and is ready again to fully respond to the agonist

48
Q

name 3 well established second messengers

A

cAMP
Ca2+
cGMP

49
Q

what does cAMP stand for

A

cyclic adenosine monophosphate

50
Q

true or false

cAMP is a second messenger

A

true

51
Q

when and where is cAMP released?

A

released in the cytoplasm due to hormone binding

52
Q

explain the function of 2nd messengers

A

they can activate many cell activities leading to a large scale, coordinated response.

53
Q

2nd messenger mechanism - cAMP

A

-agonist binds
-this activates Gs and Adenylyl Cyclase. ATP converted to cAMP by Adenylyl cyclase.

cAMP converted to AMP by PDEs (phosphodiesterases)

cAMP kinase: consists of catalytic region and regulatory region. cAMP binds to the regulatory sites and the catalytic regions are released.

catalytic regions + ATP will phosphorylate the substrate leadinf to a CELLULAR RESPONSE:

-enzyme activation
-protein synthesis
-muscle relaxation
-nerve stimulation
-hormone secretion

54
Q

what is the function of AC in the mechanism of second messengers

A

AC = adenylyl cyclase

converts ATP to cAMP

55
Q

what does cAMP get converted to and by what

A

cAMP is converted to AMP by PDEs (phosphodiesterases)

56
Q

explain the structure and role of cAMP kinase

A

consists of 2 regulatory regions and 2 catalytic regions.

cAMP binds to the regulatory sites which releases the catalytic regions.

these catalytic regions + ATP phosphorylate the substrate to produce a cellular response

57
Q

explain the cellular response produced by cAMP

A

-enzyme activation
-protein synthesis
-muscle relaxation
-nerve stimulation
-hormone secretion

58
Q

true or false

cAMP causes muscle stimulation

A

false - muscle relaxation

59
Q

true or false

cAMP causes nerve stimulation

A

true

60
Q

true or false

cAMP causes enzyme activation

A

true

61
Q

true or false

cAMP causes protein degradation

A

false - protein synthesis

62
Q

true or false

cAMP causes hormone secretion

A

true

63
Q

what is the mechanism of viagra

A

phosphodiesterase inhibitor.
this will prevent the conversion of cAMP to AMP

this will increase cAMP causing an increase in downstream signaling and vasodilation (muscle relaxation)

64
Q

in the mechanism of cAMP, what happens when the agonist dissociates?

A

the intracellular actions of cAMP are terminated by 3 mechanisms:

-GTP hydrolyzed back to GDP

-the activation of cAMP kinase is inhibited. the Tetramer is re-established

-the phosphorylated substrate (generated by cAMP kinase) is dephosphorylated (BY PHOSPHATASES), causing a DIMINISHED CELLULAR RESPONSE

65
Q

What is the effect of caffeine on cAMP levels?

A

caffeine acts as a competitive inhibitor of phosphodiesterases, thus INCREASING CAMP LEVELS

66
Q

Besides caffeine, what drugs increase cAMP levels?

A

theophylline (bronchodilator used for asthma treatment)

methylxanthine drugs

67
Q

what substances are COMPETITIVE INHIBITORS of PDEs? (phosphodiesterases)

A

caffeine and theophylline

methylxanthine drugs are non competitive inhibitors of phosphodiesterases

68
Q

true or false

caffeine, theophylline, and methylxanthine drugs all increase intracellular cAMP levels

A

true

69
Q

name 5 effects of methylxanthine drugs

A
  • increased CNS activity (increased alertness, deferral of fatigue)

-increase in inotropic effect of the heart (increase force)

-increased gastric acid secretion and increased enzymes (in GI)

  • decreased Na reabsorption and increased glomerular filtration (thus they are weak diuretics!)

-increased bronchodilation (used for asthma treatment!)

70
Q

true or false

methylxanthines decrease heart contraction

A

false - increase

71
Q

true or false

methylxanthines increase gastric secretion and enzymes in the GI tract

A

true

72
Q

true or false

methylxanthines decrease sodium reabsorption

A

true

also increase glomerular filtration – weak diuretics

73
Q

what effect do methylxanthines have on the CNS?

A

increased CNS activity leading to increased alertness and deferral of fatigue

74
Q

what is(are) the second messenger(s) involved in Gq coupled receptors

A

calcium and phosphoinositides

75
Q

name 4 receptors that are Gq coupled

A

acetylcholine (muscarinic)
alpha1-adrenergic
platelet activating factor
serotonin (5-HT1C and 5-HT2)

76
Q

When a ligand is bound to Gq, what 2nd messenger is likely involved?

A

calcium

77
Q

explain the mechanism of calcium as a second messenger

A

agonist binds, Gq protein is stimulated and binds GTP.

PLC activates PIP2 which activates DAG and IP3. IP3 releases CALCIUM. this calcium binds and activates CALMODULIN.

calmodulin (with bound calcium) then stimulates signaling through calcium/calmodulin dependent protein kinases to PHOSPHORYLATE THE SUBSTRATE AND PRODUCE A CELLULAR RESPONSE

meanwhile, while IP3 released calcium, DAG remains in the membrane where it binds and activates PKC (protein kinase C) which phosphorylates certain substrates to produce a cellular response – INCREASED GLAND SECRETION, CELL GROWTH AND DIFFERENTIATION, AND INCREASED METABOLISM

78
Q

how does PKC become active and what happens when it is activated

A

DAG binds and activates PKC.

PKC can then phosphorylate certain substrates to produce a cellular response

79
Q

what cellular responses occur when PKC phosphorylates its substrates

A

increase gland secretion
increased cell growth and differentiation
increased metabolism

80
Q

what does cGMP stand for

A

cyclic guanosine-3’,5’-monophosphate

81
Q

explain where cGMP plays a role as a second messenger

A

only in a few cell types like intenstinal mucosa and vascular smooth muscle

82
Q

explain whne cGMP-based signal transduction is initiated.

in which cells does this occur?

A

in intestinal mucosa and vascular smooth muscle when:

-ligand binds to the extracellular domain of the receptor

-ligand binding stimulates intracellular guanylyl cyclase activity

-cGMP activates cGMP-dependent protein kinases

83
Q

what is cGMP produced from and how?

A

GTP becomes cGMP through guanylyl cyclase

guanylyl cyclase activity is stimulated when the ligand binds to the extracellular domain of the receptor

84
Q

what does cGMP do

A

it activates cGMP dependent protein kinases

these activated kinases then phosphorylate the substrate

85
Q

increased cGMP causes….

A

relaxation of vascular smooth muscle

86
Q

HOW does cGMP cause the relaxation of vascular smooth muscle?

A

by a kinase-mediated mechanism that results in the DEPHOSPHORYLATION of myosin light chains

87
Q

name 2 specific things that will result in increased cGMP accumulation

A

-ANP binds to its receptor which increases guanylyl cyclase activity. guanylyl cyclase converts GTP to cGMP

-lipid souble gas NO (nitric oxide) is released by nearby vascular endothelial cells which DIRECTLY ACTIVATES guanylyl cyclase (binds to it and activates)

88
Q

several _____ drugs mimic NO (nitric oxide)

A

vasodilator

89
Q
A

Pharmacology Midterm (edit) (12 decks)

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