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Molecular And Cellular Pharmacology > Cyclic AMP > Flashcards

Cyclic AMP Flashcards

1
Q

What GPCRs increase adenylyl cylase activity?

A

Beta 1,2,3

D1, D5

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2
Q

What GPCRs decrease adenylyl cyclase activity?

A

M2,4
Alpha 2
GABAb

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3
Q

What can cAMP go on to modulate?

A

Cyclic nucleotide regulated GEFs
PKA
Cyclone nucleotide gated channels

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4
Q

How many isoforms of AC are there?

A

10 but only 1-9 are membrane bound

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5
Q

What isoform does G(alpha)i actually increase AC activity?

A

AC2

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6
Q

Which isoform is activtated by calcium calmodulin?

A

AC1

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7
Q

Which isoform is inhibited by calcium?

A

AC5

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8
Q

Structure of AC?

A 
Intracellular N terminus
M1 (consists of 6 TMDs)
Intracellular C1 (forms catalytic domain)
M2 (consists of 6 TMDs)
C2 (forms catalytic domain)
Intracellular C terminus
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9
Q

What are the importance of C1 and C2 domains?

A

Both are homologous domains with catalytic activity and site of enzymes

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10
Q

What regulates AC activity?

A

The Ga subunit
Sometimes calcium
PKA and PKC

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11
Q

Why are different regulatory processes and numerous isoforms of AC and PDE’s important?

A

Cell is continually interpreting signals and this allows for cross talk between different pathways
Cells specific responce to extracellular signals depend on isoform they have

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12
Q

What does Gai, BY and Gas bind to on AC?

A

Gai - C1
BY - C1 + 2
Gas - C1 + 2

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13
Q

How many families of phosphodiesterase are there?

A

11

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14
Q

Which PDE are specific for degrading cGMP?

A

5,6 and 9

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15
Q

Which PDE are specific for degrading cAMP?

A

4,7 and 8

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16
Q

What PDE are non specific for the cyclic nucleotides?

A

1,2,3,10 and 11

17
Q

Where does PKA phosphorylate?

A

Serine and theonine residues
However, it also recognises proximal amino acids and distal aminoacids ‘consensus recognition sequence’. This sequences is essential for phosphorylation to occur

18
Q

What is the structure of inactive type 1 PKA?

A

2 regulatory subunits (4 isoforms exist) and 2 catalytic subunits (3 isoforms exist (alpha, beta and gamma))

19
Q

Why is the benefit of a number of isoforms for the regulatory and Catalytic subunits?

A

Can form different hetromultimers

Different patterns of expression and sub-cellular localisation in involved in different cellular processes

20
Q

How is type 1 PKA activated?

A

4 Camps binds to regulatory subunit (forming the regulatory subunit dimer) of PKA which causes the release of two catalytic subunit monomers

21
Q

What is the effect of phosphorylation of proteins?

A

Changes activity of proteins

Changes affinity for associated proteins which can regulate subcellular location

22
Q

What is PKA type 2?

A

The regulatory subunit is bound to A kinase anchoring protein (AKAP) which helps for a protein complex between PKA and it substrate. This is localised to the cellular target of the substrate

23
Q

How is PKA 2 activated?

A

4 cAMPs bind to regulatory subunit which opens up the catalytic subunit to phosphorylate the substrate

24
Q

What is the advantage of AKAP bound PKA?

A

Everything is localised which allows for quick, efficient and specific phosphorylation

25
Q

Name some examples of PKA targets

A

NT synthesis
In heart will increase ionotropic and chronotropy
Ion channels (AMPA at s845)
Regulation of enzymes and proteins

26
Q

What does DARPP-32 stand for?

A

Dopamine and cAMP regulated phosphoprotein of 32KDa

27
Q

In the DARPP-32 system what effect does PKA have?

A

Phosphorylated DARPP-32 at Threonine 34 which inhibits protein phosphatase 1
PKA activates protein phosphatase 2A which dephosphorylates DARPP-32 at theonine 75. T75 phospho DARPP-32 inhibits PKA thus PKA attenuates PKA inhibition

This promotes kinase activity over phosphatase activity

28
Q

What phosphorylates DARPP-32 at tyrosine 75?

A

CDK5

29
Q

IN the DARPP-32 system what activates PKA?

A

Activation of the adenosine A2A receptors increases Gas and increases cAMP

30
Q

What is the effect of caffeine on the DARP-32 system?

A

Inhibits the adenosine receptors in the nucleus accumbens
Therefore, DARPP-32 is not phospho at T34 and pp1 is not inhibited
Also, PP2A not activated which leaves T75 phospho DARPP-32 to inhibit PKA

Phosphatase activity > Kinases activity

31
Q

What are cyclic nucleotide gated channels? Where might they be found?

A

Intracellular Cyclic nucleotides regulate channel opening
E.g. In the pacemaker cells in heart
Retinal rod cells (cGMP)
Structurally similar to VG K+ channels

32
Q

What does EPAC stand for?

A

Exchange protein directly activated by cAMP

33
Q

How many EPAC isofroms are there?

A

2
EPAC 1 - mRNA found extensively
EPAC 2 - mainly in brain

34
Q

What is the function of EPACs?

A

Have guanine nucleotide exchange factor properties which activates small GTPases such as RAP1 these then go on to signal cell adhesion via intergrins

35
Q

How does cAMP activate EPAC?

A

EPAC N ermines contains regulatory domain which acts to autoinhibit the catalytic domain (closest to C terminus)
CAMP binds to the regulatory domain to causes a confirmational change which releases EPAC from auto inhibition (independent of PKA)

36
Q

List two functions of EPACs?

A

Role depends on cell type
BetaAR in heart = regulation of cardiac myocyte hypertrophy (RNAi KO of EPAC = hypertrophy)
GLP-1R in pancreas regulates insulin secretion target for hypoglycaemic agents

37
Q

What are the various way a cell creates a micro domain?

A

Calveolae
Lipid rafts
AKAP (AKAP-79 binds B2AR to PKA)
Localised PDE - restricts diffusion of cAMP which leads to localised response
Different isoforms of proteins - regulated differently and localised to different compartment. Responce of cell dictated by what isoform it expresses

38
Q

Within cardiac muscle, what does PKA do?

A

Phosphorylates L type ca2+ channels (Increases activity)
Phosphorylates Ryanodine receptor. PKA is localised to SER (increases channel conductance)
Phospho of tropnin I (increases calcium sensitivity and increases rate of relaxation)
Phospho of BAR (desensitisation - neg feedback mechanism)
Phosphorylates phospholamban which increases SERCA2 activity)

39
Q

Why is the increase in cAMP localised to near the SER in cardiac muscle?

A

Surrounded by PDE which attenuate global cAMP signal

Molecular And Cellular Pharmacology (12 decks)

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