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BS3054 > 21st Oct - cAMP > Flashcards

21st Oct - cAMP Flashcards

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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

Study These Flashcards
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

Study These Flashcards
A

Tyrosine hydroxylase expression is increased by PKA

25
Give an example of a GPCR targeted by PKA
Beta adrenoceptor | M1 muscarinic receptor
26
Give an example of an ion channel targeted by PKA
AMPA and NMDA
27
Give an example of a cytoskeletal protein targeted by PKA
microtubule associated proteins expression is increased by PKA
28
Give an example of a TF targeted by PKA
cAMP response element binding protein (CREB)'s activity is increased by PKA
29
Give an example of a protein phosphatase inhibitor targeted by PKA
DARPP-32
30
What is DARPP-32
A regulator of both PKA and PP1 which modulates dopaminergic signalling, dependent upon where it is phosphorylated
31
Give 2 signalling mechanisms to show the effect of caffeine
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
Give some physiological roles of cyclic nucleotide gated ion channels
Olfactory Dark Current in retinal rod cells Heart pacemaker cells
33
What is EPAC?
Exchange protein directly activated by cAMP, which functions as a GEF for Ras-like small GTPases Rap1 and Rap2
34
When was EPAC discovered?
1988
35
Why could EPAC be important therapuetically?
It is a PKA independent method of cAMP signalling
36
Outline the conformational change upon EPAC activation
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
What are the main receptors that activate EPAC?
Glucagon Like Peptide -1 Receptor Dopamine receptor Beta adrenoceptors
38
What are caveolae?
Little caves in the membrane which create spatial localisation of signalling molecules
39
What are the functions of PKA in cardiac function?
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
Where are PDEs localised in cardiac myocytes?
Near the sarcoplasmic reticulum
41
Who popularised the concept of comparmentalised signalling pathways in the 1980s?
Brunton and colleagues with spatial cAMP segregation in cardiac myocytes
42
What enzyme is important for cGMP localisation?
PDE PDE5 for sGC derived cGMP PDE2 for pGC derived cGMP
43
How is NO localised?
By localising NOS to the plasma membrane thus localising NO production, and ensuring that Ras activation is limited to the plasma membrane
44
Where can Calcium be localised?
In caveolae which can function as mini calcium stores which release calcium in an ATP dependent manner
45
How are cAMP microdomains formed?
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
Where were the first cyclic nucletotide gated ion channels discovered?
Retinal Rod Photoreceptors
47
What is CatSper?
The cation channels of sperm that regulate sperm motility
48
Outline the basic domain structure of AKAPs
Contain a PKA binding tethering domain and a unique targeting domain
49
What is Ht31?
A competitive antagonist against AKAPs. | Anchoring disruption peptide which mimics the ampthipathic helix of AKAPs
50
Outline the Beta adrenergic receptor function in cardiac myocytes
Gs pathway | -PKA phosphorylates RyR, troponin 1, phospholamban (causing an increase in SERCA2) and myosin binding protein C
51
What are the AKAPs important in cardiovascular function?
AKAP 79 --> Beta adrenoceptor | AKAP 18 alpha --> L-type calcium channels
52
What are the important AKAPs in sperm?
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
Outline the role of PKA in metabolism in adipocytes
Hormone sensitive lipase drives hydrolysis of triglycerides this is dramatically increased by PKA phosphorylation of hormone sensitive lipase.
54
What is the tissue localisation of EPAC 1?
``` Heart Brain Pituitary Ovaries Thyroid gland ```
55
What is the tissue localisation of EPAC 2?
Brain Pituitary Adrenal Gland
56
Outline the signalling pathway of EPAC in vascular smooth muscle cells
EPAC --> Rap --> migration and proliferation --> neointima thickening
57
How does EPAC have an anti-inflammatory effect?
It inhibits endothelial leukocyte migration

BS3054 (25 decks)

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