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Pharmacology > cGMP > Flashcards

cGMP Flashcards

1
Q

What is cGMP derived from?

A

GTP

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2
Q

How are most of cGMP’s effects mediated?

A

Through PKG

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3
Q

cAMP can signal via Epacs. Does cGMP have an equivalent?

A

No

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4
Q

Which enzyme synthesises cGMP?

A

Guanylyl Cyclase

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5
Q

Guanylyl Cyclases are regulated by a diverse range of agonists. Give some examples.

A
  1. peptide hormones
  2. bacterial toxins
  3. free radicals (eg NO)

…also regulated indirectly by intracellular calcium

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6
Q

GCs and cGMP-mediated signalling cascades play a central role in the regulation of a diverse range of physiological processes. Give 3 examples.

A
  1. vascular smooth muscle contractility
  2. intestinal fluid and electrolyte homeostasis
  3. phototransduction
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7
Q

What are the two main families of Guanylyl Cyclases?

A
  1. Particulate GCs (membrane bound)

2. Soluble GCs (cytosolic/ NO-sensitive)

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8
Q

Both GC families are ubiquitous. What does this mean?

A

They are found in (almost) every cell type

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9
Q

Membrane bound (particulate) guanylyl cyclases exist in how many isoforms in mammals?

A

seven

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10
Q

How many isoforms of pGC are there? How are they denoted?

A
  1. GC-A to GC-G
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11
Q

What does pCG stand for?

A

Particulate guanylyl cyclase

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12
Q

pGCs exhibit a highly conserved domain structure. Give 4 features.

A
  1. Extracellular binding domain at N-term
  2. Single TM domain
  3. Regulatory subunit with significant homology to protein kinases
  4. C-term catalytic domain
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13
Q

Where is the catalytic domain located in pGCs?

A

In the C-teminus

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14
Q

How do pGCs become catalytically active?

A

Dimerisation

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15
Q

How does the catalytic domain of pGCs compare to that of ACs?

A

Structurally and functionally homologous

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16
Q

Based on ligand specificities, pGCs have been classified into three classes. What are these?

A
  1. Natriuretic peptide receptors
  2. Intestinal peptide-binding receptors
  3. Orphan receptors
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17
Q

Which class do pGC-A and pGC-B fall into?

A

The class of Natriuretic peptide receptors

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18
Q

Which pGCs are in the natriuretic peptide receptor class? What are they activated by?

A

GC-A and GC-B

They are activated by ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide)

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19
Q

Which pGC falls into the Intestinal Peptide-Binding Receptors class? What is it activated by?

A

GC-C

Activated by guanylin, uroguanylin

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20
Q

Which class of receptors do the pGC-C, -D, -E, -F, and -G fall into?

A

Orphan receptors

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21
Q

What is the structure of soluble GCs? (sGCs)

A

They are heteroDIMERIC proteins consisting of one alpha and one beta subunit

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22
Q

How many isoforms of sGC exist?

A

Multiple: 3 alpha subunit isoforms and 3 beta subunit isoforms

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23
Q

What do the alpha and beta subunits of GC consist of?

A

N-term regulatory domain (contains heme binding and dimerisation region)
C-term catalytic domain

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24
Q

Which domain of sGCs contains the heme binding and dimerisation regions?

A

N-term domain (regulatory)

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25
Q

Where are sGCs expressed?

A

In the cytoplasm of almost all mammalian cells

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26
Q

sGCs mediate a wide range of physiological functions. Give 4 examples.

A
  1. inhibition of platelet aggregation
  2. relaxation of smooth muscle
  3. neuronal signal transduction
  4. immunomodulation
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27
Q

Which group is required by sGCs in order to be activated by NO?

A

Heme

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28
Q

Where does Heme bind on sGC?

A

To the regulatory N-terminal domain

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29
Q

Which two things are sGCs activated by? Which is more potent.

A
  1. Nitric oxide (NO), a free radical
  2. Carbon monoxide (CO)
    NO IS FAR MORE POTENT
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30
Q

How does NO activate sGCs?

A

By binding directly to the heme group

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31
Q

Give an example of a receptor associated with both PKA and PKG (in different cell types)

A

IP3

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32
Q

Which enzyme mediates the majority of the cellular effects of cGMP?

A

PKG (serine/threonine kinase)

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33
Q

How many classes of PKG exist?

A

2

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34
Q

How do Type I and Type II PKGs differ in expression?

A

Type I expressed in many cell types

Type II less common and only expressed in INTESTINE, KIDNEY, BRAIN

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35
Q

Type I PKGs are expressed in many cell types. Type II PKGs, however, are only expressed in 3 organs. What are these?

A

Intestine
Kidney
Brain

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36
Q

How many isoforms of Type I PKG exist?

A

2 (Type I-alpha, and Type I-beta)

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37
Q

Type I PKGs exist as homodimers. Which 3 domains does each subunit contain?

A
  1. a dimerisation domain
  2. 2 x cGMP-binding domains
  3. an autophosphorylation-autoinhibitory domain
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38
Q

Where in the cell are Type I PKGs located?

A

In the soluble fraction

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39
Q

Type I PKGs are homodimeric. What are Type II PKGs?

A

Monomeric kinases

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40
Q

What is the structure of Type II PKGs?

A
  1. catalytic domain at C-terminal
  2. 2 x cGMP-binding domains at N-terminal
  3. generally membrane-bound
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41
Q

Where in the cell are Type II PKGs usually found?

A

Bound to the membrane

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42
Q

Give 4 examples of proteins regulated by PKGs

A
  1. IP3 receptor
  2. IRAG
  3. Calcium-activated maxi K+ channel
  4. PP1M (the myosin light chain phosphatase)
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43
Q

How does PKG regulate the IP3 receptor?

A

Causes calcium release from internal stores

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44
Q

What is the result of PKG regulation of IRAG?

A

Inhibits calcium release from internal stores

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45
Q

What does IRAG stand for?

A

IP3-Receptor Associated cGMP kinase substrate

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46
Q

PKG has not been found to regulate transcription factors. What is the proposed reason for this?

A

Too large to enter the nucleus

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47
Q

Whilst PKG is too large to enter the nucleus and interact with transcription factors, it is able to affect gene transcription indirectly. How?

A

By phosphorylating cytoplasmic proteins

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48
Q

In addition to PKG, give two other effectors of cGMP

A

CNG channels

Phosphodiesterases

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49
Q

CNG channels can be activated by different cyclic nucletide to regulate 1) visual transduction and 2) olfaction. Which cyclic nucleotide is each CNG isotope more sensitive to?

A

1) visual transduction - cGMP

2) olfaction - cAMP

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50
Q

Which superfamily of ion channels do CNG channels belong to?

A

Voltage-gated ion channels

51
Q

What are HCN channels?

A

Hyperpolarisation-activated Cyclic Nucleotide-gated channels

52
Q

Hyperpolarisation-activated Cyclic Nucleotide-gated (HCN) channels are a subfamily of which class of channels?

A

CNG channels

53
Q

In which two organs are HCN channels expressed?

A

Brain and Heart

54
Q

How are HCN channels modulated?

A
  1. binding of cyclic nucleotides

2. hyperpolarisation

55
Q

Give an example of the function of HCNs.

A

In pacemaker currents in the sinoatrial (SA) Node

56
Q

How many different families of PDEs exist in mammals?

A

At least 11

57
Q

How many PDE enzymes exist in humans?

A

> 30

58
Q

Which PDE families hydrolyse:

  1. BOTH cGMP and cAMP
  2. cAMP only
  3. cGMP only
A

1) 1, 2, 3, 10, 11
2) 4, 7, 8
3) 5, 6, 9

59
Q

Which families of PDEs hydrolyse both cGMP and cAMP?

A

1, 2, 3, 10, 11

60
Q

Which families of PDEs hydrolyse only cGMP?

A

5, 6, 9

61
Q

Which families of PDEs hydrolyse only cAMP?

A

4, 7, 8

62
Q

Give three main factors that can regulate phosphodiesterases

A

1) substrate availability (e.g. alteration in the rate of hydrolysis of one cyclic nucleotide because of competition by another)
2) intracellular signalling events (e.g. phosphorylation, Ca++)
3) feedback regulation

63
Q

How are PDEs regulated by intracellular signalling events?

A

1) PDE3 stimulated by insulin
2) PDE6 stimulated by photons through transducin system
3) PDE1 stimulated by Ca++/calmodulin

64
Q

Which PDEs are phosphorylated (and thus regulated) by PKA after cAMP regulation?

A

PDE1
PDE3
PDE4

65
Q

How does cAMP elevation affect PDEs?

A

PDE1, -3 and -4 are phosphorylated by PKA after cAMP elevation

66
Q

How does cGMP promote its own breakdown after its elevation?

A

It binds to allosteric sites on PDE2

67
Q

Which PDE is critical in photo transduction, and which cyclic nucleotide does it act on?

A

PDE6

controls cGMP

68
Q

The tone of smooth muscle depends upon a balance between contractile and relaxation mechanisms. Which signalling pathway plays a fundamental role in controlling relaxation?

A

The NO/cGMP signalling pathway

69
Q

How does the NO/cGMP pathway control relaxation of smooth muscle cells?

A

By acting at a number of sites concerned with calcium-signalling

70
Q

How do exagenous and endogenous compounds such as nitro-vasodilators, NO and natriuretic peptides produce vasodilation?

A

Through increases in cGMP

71
Q

What is the effect of cGMP activation of PKG on vascular smooth muscle? How>

A

It relaxes it by:

1) reducing intracellular calcium and promoting the activity of myosin light chain phosphatase (MLCP) through a direct phosphorylation by PKG, and
2) inhibiting RhoA (which inhibits MLCP through activating ROCK)
3) activates RGS2 which inhibits Galphaq signalling

72
Q

Which RGS protein inhibits G-alpha-q signalling?

A

RGS2

73
Q

How does activation of PKG by cGMP result in inhibition of G-alpha-q signalling?

A

It activates RGS2

74
Q

How does inhibition of RhoA help to relax smooth muscle?

A

Because RhoA inhibits MLCP through the action of the protein ROCK

75
Q

What is the main mechanism through which cGMP reduces Ca++?

A

It activated PKG, which phosphorylates target proteins

76
Q

cGMP reduces Ca++ principally through the action of PKG phosphorylation of target proteins. What three things does this result in?

A

1) inhibition of Ca++ influx through L-type calcium channels (by activating BK(Ca) channels)
2) increased Ca++ efflux through activation of Ca2+-pumping and Na+/Ca2+ exchanger
3) decreased Ca2+ mobilisation through inhibition of the IP3 receptor in the sarcoplasmic reticulum by activation of IRAG

77
Q

What does IRAG stand for?

A

IP3 Receptor-Associated PKG substrate

78
Q

What is the commercial name for sildenafil citrate?

A

Viagra

79
Q

What is viagra used to treat?

A

Male erectile dysfuction (impotence) and pulmonary arterial hypertension

80
Q

What does the physiological process of erection involve?

A

The release of nitric oxide (NO) in the corpus cavernosum of the penis resulting in smooth muscle relaxation and an increased inflow of blood

81
Q

How does nitric oxide cause relaxation of the smooth muscle of the penis? (i.e. result in an erection)

A
  1. NO activates GC
  2. GC produces an increase in [cGMP]i
  3. cGMP reduces [Ca2+]i (mainly through PKG phosphorylation of target proteins)
  4. cGMP desensitises the contractile apparatus to Ca2+
  5. blood flows into the penis and it becomes erect
82
Q

How does Sildenafil (VIAGRA) work?

A

It enhances the level of cGMP

83
Q

How does viagra enhance the level of [cAMP]i?

A

Inhibiting the cGMP-specific PDE5, which hydrolyses cGMP to 5’GMP

84
Q

Which enzyme does Viagra inhibit to enhance levels of cGMP?

A

PDE5

85
Q

How does sildenafil (viagra) inhibit PDE5?

A

It has a structure very similar to cGMP, and acts as a competitive inhibitor

86
Q

What is the structure of PDE5?

A

It is a homodimer with each subunit containing:

1) a regulatory phosphorylation site (Ser92),
2) two allosteric cGMP binding sites,
3) two Zinc-binding motifs, and
4) a catalytic binding site

87
Q

Which residue is phosphorylated in the regulatory site of PDE5?

A

Ser92

88
Q

How many allosteric cGMP binding sites are there in PDE5?

A

2

89
Q

How many zinc-binding motifs are there in PDE5?

A

2

90
Q

Which cyclic nucleotide does PDE5 act on?

A

cGMP

91
Q

What is necessary for Ser92 phosphorylation of PDE5 by PKA/PKG?

A

Occupation of the two allosteric cGMP binding sites

92
Q

Which residue is phosphorylated by PKA/PKG on PDE5?

A

Ser92

93
Q

How does phosphorylation of Ser92 affect PDE5 activity?

A

It increases enzyme activity by 50-70%

94
Q

Where is the catalytic domain of PDE5 located?

A

C-terminus

95
Q

At high doses, viagra can inhibit another enzyme in addition to PDE5. Which is this?

A

PDE6

96
Q

Which enzyme can be inhibited (in addition to PDE5) by high doses of viagra? Where is this enzyme located?

A

PDE6. It is found in the retina

97
Q

In addition to male erectile dysfunction (impotence), what has Viagra been approved for the treatment of?

A

Pulmonary arterial hypertension

98
Q

What does ‘Matching’ describe?

A

Normal lung function requires blood to be directed to well ventilated areas of the lungs to ensure optimal gas exchange (‘Matching’)

99
Q

Normal lung function requires blood to be directed to well ventilated areas of the lungs to ensure optimal gas exchange. What is this called?

A

Matching

100
Q

What is lung vessel dilation mainly regulated by?

A

NO/cGMP

101
Q

During disease conditions, malfunction of vasodilation of lung vessels can cause ‘Mismatch’. What does this mean?

A

Blood is directed to poorly ventilated areas

102
Q

Which PDE is highly expressed in lungs?

A

PDE5

103
Q

What effect can sildenafil have in the lung? Why?

A

Anti-pulmonary hypertensive effect by preferentially dilating vessels in well oxygenated areas of the lung through targeting PDE5

104
Q

Why is sildenafil sometimes referred to as a ‘re-matching’ drug?

A

It acts on PDE5 to preferentially dilate vessels in well oxygenated areas of the lung

105
Q

What does cGMP stand for?

A

cyclic guanosine monophosphate

106
Q

NO has multiple biological effects. List 4.

A
  1. nitrosylation of proteins
  2. direct toxic effects
  3. induction of protein ADP-ribosylation
  4. stimulation of soluble guanylyl cyclase
107
Q

Which type of enzyme does NO act on?

A

SOLUBLE guanylyl cyclase

108
Q

Which enzyme synthesises NO?

A

Nitric oxide synthase (NOS)

109
Q

How many types of nitric oxide synthase are there?

A

3

110
Q

What are the different types of nitric oxide synthase?

A

iNOS: inducible (toxic)
eNOS: endothelial (signalling)
nNOS: neuronal (signalling)

111
Q

Which NOS produces HIGH NO concentrations that can exhibit direct toxic effects?

A

iNOS (INDUCIBLE NOS)

112
Q

How does NOS produce NO?

A

It catalyses oxidation of an amidine nitrogen of L-arginine, generating NO and citrulline

113
Q

NOS produces NO from L-arginine. What else is produced?

A

Citrulline

114
Q

How does NOS change L-arginine to make NO?

A

Oxidises an amidine nitrogen

115
Q

How does PKG Type I differ from PKG type II?

A

1) homodimeric vs monomeric
2) ubiquitous vs intestine/kidney/brain
3) diffuse in soluble part of cell vs membrane-bound

116
Q

Give an example of NO/GC/cGMP/PKG in action

A

Vasoregulation

117
Q

How does calcium regulate vascular tone?

A

1) IP3 produced and calcium released from intracellular stores, followed by external calcium entry
2) rise in calcium activates calcium/calmodulin dependent MLCK (phosphorylates MLC resulting in activation of myosin ATPase)
3) fall in calcium inactivates MLCK and causes dephosphorylation of MLC by MLCP (aka PP1M)

118
Q

What is the effect of a rise in calcium on myosin light chain kinase (MLCK)? How is this mediated?

A

The rise in calcium activates calcium/calmodulin-dependent MLCK

119
Q

What is the effect of Ca/calmodulin-dependent MLCK activation?

A

Phosphorylation and thus activation of myosin ATPase

120
Q

How does a fall in Ca result in dephosphorylation of MLC (and thus inactivation of myosin ATPase)?

A

Inactivated MLCK which causes MLCP (PP1M) to dephosphorylate MLC

121
Q

What effect does PKG have on intracellular calcium levels?

A

Decreases, i.e. through activation of RGS2, which attenuates Galpha(q) signalling

122
Q

Where on PDE5 does viagra bind?

A

at the CATALYTIC not the allosteric sites (competes with the binding of cGMP)

123
Q

Viagra prompted other companies to produce alternative drugs. Give two examples.

A

Cialis - long-lasting effect

Levitra - works in less time than Viagra

124
Q

Viagra has been proven to be effective in treating male impotence and pulmonary arterial hypertension. What else can it be used for?

A

Altitude sickness

Pharmacology (13 decks)

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