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BS3054 > 21st Oct - cAMP > Flashcards

21st Oct - cAMP Flashcards

1
Q

What was the first second messenger to be identified?

A

cAMP

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2
Q

What is the full name of cAMP?

A

Cyclic adenosine mono-phosphate

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3
Q

What are the three main effectors of cAMP?

A

PKA
EPAC
cAMP gated ion channels

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4
Q

What are the two enzymes that regulate the levels of cAMP?

A

adenylyl cyclase and phosphodiesterase

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5
Q

What are AKAPs?

A

A-kinase anchor proteins that bind to the regulatory subunit of PKA

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6
Q

What are the main functions of PKA?

A

Inactivate PLC beta
Decrease Raf and Rho activity
Modulate ion channel permeability
Transcriptional regulation by phosphorylating CREB and CREM

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7
Q

What counterbalances the actions of PKA?

A

PP1 and PP2A

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8
Q

What is the function of EPAC?

A

It is a GEF for small GTPases

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9
Q

What are the major pathways that stimulate cyclic nucleotide formation?

A

Galpha s –> AC –> cAMP –> PKA

NO -> GC –> cGMP –> PKG

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10
Q

Give an example of a Gs linked receptor

A

H2 Histamine receptor
Adrenoceptors B1/B2/B3
Dopamine receptors D1/D5
Serotonin receptors 4/6/7

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11
Q

Give an example of a Gi linked receptor

A 
M2/m4 AChR
alpha2 A-D adrenoceptors
D2/D3/D4 dopamine receptors
Serotonin receptors 1A/B/D/F
GABAB
mFluR 2/3/4/6/7/8
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12
Q

How many mammalian isoforms are there of adenylyl cyclase?

A

10

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13
Q

Outline the structure of adenylyl cyclase

A

1 protein
2 TM regions M1 and M2 each with 6 helices
2 homologous cytoplasmic domains C1 and C2
C1 and C2a interact to create the active site

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14
Q

Outline the main ways of regulating adenylyl cyclase

A

Stimulation by: G alpha s, GBetagamma (e.g. AC2), Calmodulin (e.g. AC1), PKC, (Forskolin pharmacological)

Inhibition by: G alpha i, Gbeta gamma (e.g. AC1), calcium ions (e.g. AC5), PKA

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15
Q

How many families of PDE are there in mammals?

A

> 11

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16
Q

What are the three main types of PDE?

A

Hydrolyses both cGMP and cAMP (1,2,3,10 and 11)
Hydrolyses cAMP preferentially (4,7 and 8)
Hydrolyses cGMO (5,6 and 9)

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17
Q

What is the main method of regulating PDEs?

A

Kinases

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18
Q

What is PKA?

A

A serine/threonine kinase

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19
Q

How is PKA activated?

A
  1. The catalytic subunits are bound by the regulatory subunits inhibiting them from binding
  2. 4 cAMP molecules bind to PKA
  3. Regulatory subunits dissociate allowing the catalytic subunits to phosphorylate downstream proteins
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20
Q

What are the 2 main classes of PKA?

A

PKA1

PKA2

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21
Q

Describe the class PKA1

A

Mainly free in the cytoplasm
High affinity for cAMP
Low affinity for AKAPs

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22
Q

Describe the PKA2 class

A

Usually docked to AKAPS localising it to specific targets

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23
Q

Give 5 main examples of PKA targets

A 
Neurotransmitter biosynthesis
GPCRS
Ion channels
Cytoskeletal proteins
TFs
Protein phosphatase and kinase inhibitors
24
Q

Give an example of an enzyme target by PKA involved in neurotransmitter biosynthesis

A

Tyrosine hydroxylase expression is increased by PKA

25
Q

Give an example of a GPCR targeted by PKA

A

Beta adrenoceptor

M1 muscarinic receptor

26
Q

Give an example of an ion channel targeted by PKA

A

AMPA and NMDA

27
Q

Give an example of a cytoskeletal protein targeted by PKA

A

microtubule associated proteins expression is increased by PKA

28
Q

Give an example of a TF targeted by PKA

A

cAMP response element binding protein (CREB)’s activity is increased by PKA

29
Q

Give an example of a protein phosphatase inhibitor targeted by PKA

A

DARPP-32

30
Q

What is DARPP-32

A

A regulator of both PKA and PP1 which modulates dopaminergic signalling, dependent upon where it is phosphorylated

31
Q

Give 2 signalling mechanisms to show the effect of caffeine

A

W/o caffeine
Adenosine -> A2A receptor –> cAMP –> DARPP32 - T34Phos–| PP1
and cAMP–> PKA –> PP2A
–> Increase in protein phosphorylation

With caffeine
Adenosine --> A2A receptor
Caffeine -| A2A receptor
PKA inactive --> DARPP32 - T75Phosp --| PKA
PP1 active --> stimulatory effects
32
Q

Give some physiological roles of cyclic nucleotide gated ion channels

A

Olfactory
Dark Current in retinal rod cells
Heart pacemaker cells

33
Q

What is EPAC?

A

Exchange protein directly activated by cAMP, which functions as a GEF for Ras-like small GTPases Rap1 and Rap2

34
Q

When was EPAC discovered?

A

1988

35
Q

Why could EPAC be important therapuetically?

A

It is a PKA independent method of cAMP signalling

36
Q

Outline the conformational change upon EPAC activation

A
  1. In the inactive state the N-terminal regulatory region interacts with the catalytic region to inhibit GEF activity
  2. cAMP binding causes a conformational change that releases the auto-inhibition of the catalytic site thus allowing EPAC to activate the Rap GTPases
37
Q

What are the main receptors that activate EPAC?

A

Glucagon Like Peptide -1 Receptor
Dopamine receptor
Beta adrenoceptors

38
Q

What are caveolae?

A

Little caves in the membrane which create spatial localisation of signalling molecules

39
Q

What are the functions of PKA in cardiac function?

A

Reduces troponin 1s calcium sensitivity
Activates L-type Calcium channels
Activates Ryanodine receptors
Desensitises Beta adrenoceptor negative feedback loop
Phospholamban dissociates leading to an increase in SERCA2

40
Q

Where are PDEs localised in cardiac myocytes?

A

Near the sarcoplasmic reticulum

41
Q

Who popularised the concept of comparmentalised signalling pathways in the 1980s?

A

Brunton and colleagues with spatial cAMP segregation in cardiac myocytes

42
Q

What enzyme is important for cGMP localisation?

A

PDE
PDE5 for sGC derived cGMP
PDE2 for pGC derived cGMP

43
Q

How is NO localised?

A

By localising NOS to the plasma membrane thus localising NO production, and ensuring that Ras activation is limited to the plasma membrane

44
Q

Where can Calcium be localised?

A

In caveolae which can function as mini calcium stores which release calcium in an ATP dependent manner

45
Q

How are cAMP microdomains formed?

A

Via ACs and PDEs

ACs

  • membrane bound isoforms
  • CNS structure specific (AC1 and AC2 in cerebral cortex, hippocampus and cerebellum)
  • lipid rafts
  • caveolae
  • In olfactory neurons AC3 is localised to cilia

PDE

  • PDE4 targeted to beta adrenoceptor through beta arrestin
  • PDE3 targeted to Er
46
Q

Where were the first cyclic nucletotide gated ion channels discovered?

A

Retinal Rod Photoreceptors

47
Q

What is CatSper?

A

The cation channels of sperm that regulate sperm motility

48
Q

Outline the basic domain structure of AKAPs

A

Contain a PKA binding tethering domain and a unique targeting domain

49
Q

What is Ht31?

A

A competitive antagonist against AKAPs.

Anchoring disruption peptide which mimics the ampthipathic helix of AKAPs

50
Q

Outline the Beta adrenergic receptor function in cardiac myocytes

A

Gs pathway

-PKA phosphorylates RyR, troponin 1, phospholamban (causing an increase in SERCA2) and myosin binding protein C

51
Q

What are the AKAPs important in cardiovascular function?

A

AKAP 79 –> Beta adrenoceptor

AKAP 18 alpha –> L-type calcium channels

52
Q

What are the important AKAPs in sperm?

A

AKAP 82 - has dual specificity is also the main structural protein in the fibrous sheath of sperm

AKAP 220 - anchors R1 and R2 as well as PPI in sperm
-disruption of anchoring inhibits sperm motility

53
Q

Outline the role of PKA in metabolism in adipocytes

A

Hormone sensitive lipase drives hydrolysis of triglycerides this is dramatically increased by PKA phosphorylation of hormone sensitive lipase.

54
Q

What is the tissue localisation of EPAC 1?

A 
Heart
Brain 
Pituitary
Ovaries
Thyroid gland
55
Q

What is the tissue localisation of EPAC 2?

A

Brain
Pituitary
Adrenal Gland

56
Q

Outline the signalling pathway of EPAC in vascular smooth muscle cells

A

EPAC –> Rap –> migration and proliferation –> neointima thickening

57
Q

How does EPAC have an anti-inflammatory effect?

A

It inhibits endothelial leukocyte migration

BS3054 (25 decks)

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