Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Molecular And Cellular Pharmacology > Cyclic GMP > Flashcards

Cyclic GMP Flashcards

1
Q

What are the two types of guanylyl cyclase?

A 
Soluble GC (cytosolic and NO sensitive)
Particulate GC (membrane bound)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How many isoforms of pGC exist?

A

7 (A-G)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What domains does pGC have?

A 
Extracellular Ligand binding domain
Regulatory domain
Catalytic domain 
Dimerisation domain (pGC exists as homodimers)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

There are 3 groups of pGC what are they based on?

A

Their ligands
PGC A+B = bind to natriuretic peptides such as BNP which decrease TPR and increase diuresis
PGC C = binds to intestinal peptides
PGC D,E,F,G are orphan receptors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is sGC formed from?

A

Hetrodimers of 1 alpha and 1 beta subunit

Multiple isoforms of the subunits exist

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Catalytic activity of sGC is dependant on what?

A

The presence of both and alpha and beta subunit

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

SGC contains a heme group…why is this important?

A

NO (or CO) can bind here which increases endure activity by 100-200 fold

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are some functions of NO?

A 
SM relaxation
Neurotransmission
Platelet aggregation 
Stimulates sGC
Nitrosylation of proteins
Neurotoxicity
Induction of protein ADP ribosylation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How is NO formed?

A

Via Nitric oxidase synthase (nNOS, eNOS, iNOS)

This is a homodimeric protein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Why is calcium calmodulin important for NOS function?

A

Needed to aid/ complete the electron transport chain in the enzyme important for conversion of arginine + O2 -> citrulline +NO

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What does PKG do?

A

Phosphorylates serine/threonine

Dependant on upstream amino acid sequence

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Is PKG a monomeric protein?

A

No it is a homodimer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are the types of PKG?

A 
Type 1 (cytosolic)
Type 2 (membrane bound)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are the isoforms of type 1 PKG?

A

1alpha
1beta
Formed from alternative splicing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Structure of PKG monomer

A

N terminus
Regulatory domain - contains site of leucine zipper, cGMP binding and pseudosubstate
Hinge
Catalytic domain - contains ATP binding site and kinase area
C terminus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What does the pseudo-substrate of PKG do?

A

Autoinhibition via bind to kinase domain in catalytic domain area

17
Q

What is the importance eof the leucine zipper?

A

Allows dimerisation for from PKG homodimer

18
Q

What happens when cGMP binds to PKG?

A

4 cGMP bind to PKG dimer (2 for each regulatory domain)
Causes conformational change which releases pseudo-substrate from kinase area as monomers unfold.
Allows substrates to enter kinase domain and be phosphorylated

19
Q

Name come PKG functions

A

Cardiac protection
Endothelial permeability
Smooth muscle relaxation
Neuronal plasticity

20
Q

How does NO modulate vascular smooth muscle?

A 
NO is made in endothelial cells in response to endogenous ligands such as bradykinin an d shear stress 
NO diffuses into VSMC
Activates sGC
Makes cGMP which activates PKG
Relaxation
21
Q

How does PKG mediate relaxation?

A

Phosphorylates myosin light kinase phosphatase which activates it and promotes dephosphorylation of myosin light chain (relaxation)
Inhibits RhoA. Since RhoA activates ROCK which intern inhibits MLCP PKG releases MLCP from inhibition
PKG activates RGS proteins which attenuate Gaq signalling via increasing their intrinsic GTPase activity thus decreasing calcium release
Phosphorylates IRAG which regulates the IP3 R on the SER = inhibits calcium release

22
Q

Where is cGMP important for cycling nucleotide regulated ion channels?

A

Retinal rod cells
CGMP bound channels are open
Occurs during the dark state current

23
Q

What isoforms of PDE degrade cGMP?

A

Specifically 5,6, and 9

Non specifically 1,2,3,10,11

24
Q

How does cGMP regulate phosphodiesterase?

A

Alter rate of hydrolysis via competition for active site (PDE 1,2 and 3)
Allosteric modulation of activity (2,5, and 6)

25
Q

What is the drug which inhibits PDE5?

A

Sildenafil

26
Q

What is sildenafil used for?

A

Impotence

2-3 fold increase from 40 - 70

27
Q

What are other causes of erectile dysfunction?

A

Diabetes
Post prostectomy
Hypertension medication
Trauma

28
Q

How does sildenafil cause an erection?

A

Causes vasodilation of arterial vessels within the corpus cavernosum which allows cavernous sinuses to fill with blood
This then compresses the low pressure venous outflow which permits blood to remain in the penis 8====D

29
Q

Where does the No come from which initiates the erection and prolongs the erections?

A

Initiation - Neural NO

Prolongation - endothelial NO

30
Q

In terms of cellular processes how does an erection occur?

A

Cholinergic neurons activate M3 receptors on endothelial cells in repsonce to psychogenic and relfexogenic

M3 receptors are couple to Gq therefor increase in IP3 which causes calcium release

Calcium/calmodulin actives eNOS which makes NO

No defuses into SMC and forms cGMP via activation of sGC

cGMP does on to increase PKG which causes vasodilation

31
Q

In terms of cellular mechanisms how does sildenafil work?

A

In VSMC cGMP is broken down by PDE5.

Sildenafil competes for the active site for cGMP in catalytic domain of PDE5 thus preventing it breakdown. Thus, protentates amount of PKG - more vasodilation

32
Q

How can cGMP regulate PDE allosterically?

A

CGMP binds to allosteric binding sites on PDEif this occurs PKG can phosphorylate PDE at serine 92
This will increase activity of PDE so more is degraded
Mechanism by which levels of cGMP can promote its own degradation if levels get on high.

33
Q

But how much as allosteric modulation increase PDE activity?

A

50-70%

34
Q

How does PDE exist?

A

As a homodimer

35
Q

What has higher affinity for cGMP in PDE 2,5 and 6…the allosteric or catalytic site?
Why is this important?

A

Allosteric (10-50 times greater)
Means that when cGMP levels subsequently rise again cGMP will still be bound to allosteric site. Thus PDE will be available more quickly = desentisation

36
Q

What is another use of PDE5 inhibitors?

A

Pulmonary hypertension

PDE5 inhibition will cause redirection of blood flow to well ventilated areas for optimal ventilation perfusion ration

Molecular And Cellular Pharmacology (12 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions