Intracellular Signalling Pathways 2 - Effector Mechanisms

Question 1

Receptor -> G-protein -> Effector. What is the next step?

Answer 1

The effector will activate a second messenger in signalling pathways.

Question 2

Give examples of effectors.

Answer 2

Adenylyl cyclase
Phospholipase C
Phosphoinositide 3-kinase
cGMP Phosphodiesterase
or also...
Ion channels such as
Voltage-operated Ca2+ channels (VOCCs)
G-protein regulated inwardly rectifying K+ channels (GIRKs)

Question 3

What does adenylyl cyclase do?

Answer 3

ATP goes to cAMP

Question 4

What does phospholipase C do?

Answer 4

PIP2 goes to IP3 + DAG

Question 5

Explain how agonist-stimulated regulation of adenylyl cyclase work.

Answer 5

Agonist binds to GPCR. G-protein binds to activated GPCR. GDP is exchanged to GTP on the alpha subunit beta/gamma dissociates. The alpha subunit binds to adenylyl cyclase which turns ATP into cyclic AMP (cAMP)

Question 6

Which is the second messenger in adenylyl cyclase regulation?

Answer 6

cAMP.

Question 7

Give examples of Gs-coupled receptors.

Answer 7

beta-adrenoceptors
D1-dopamine receptors
H2-histamine receptors

Question 8

Explain how agonist-stimulated regulation of adenylyl cyclase work when a Gi receptor is activated.

Answer 8

Gi coupled receptor activated by agonist. Alpha I subunit’s GDP exchanged for GTP. The beta/gamma subunits dissociate. The alpha I subunit now binds to adenylyl cyclase and inhibits it. cAMP is not made.

Question 9

Give examples of Gi-coupled receptors.

Answer 9

alpha2 adrenoceptors
D2-dopamine receptors
u-opioid receptors

Question 10

What does cAMP do?

Answer 10

It binds to a protein kinase (PKA) which has regulatory and catalytic units. cAMP binds to the regulatory unit. This makes the catalytic units to dissociate and be activated. Protein kinase is now free to phosphorylate proteins in order to activate them or inhibit.

Question 11

Explain agonist-stimulated regulation of phospholipase C.

Answer 11

Gq coupled receptor activated by agonist. Alpha q subunit binds to the GPCR and GDP is exchanged for GTP. Beta/gamma subunits dissociate. Alpha Q subunit now activates phospholipase C which activates PIP2. PIP2 produces IP3 and DAG which is a second messenger. IP3 then goes to a IP3 receptor which is on the ER membrane. This makes Ca2+ to be able to leave the ER and build up in the cell. DAG goes to activate protein kinase C.

Question 12

Briefly outline the signalling pathway of inotropy in the heart when it is increased.

Answer 12

Adrenaline binds to beta1 adrenoceptor. G-s protein binds to the adrenoceptor and GDP is exchanged for GTP. beta/gamma subunits dissociate and the alpha S subunit activate adenylyl cyclase. Adenylyl cyclase turns ATP into cAMP. cAMP activates protein kinase (PKA). PKA phosphorylates a L-type VOCC channel which is then turned on so calcium ions can enter the cell. The influx of calcium creates a spark of calcium which triggers CICR to make sarcoplasmic reticulum release even more Ca2+.

Question 13

How does smooth muscle contract (vasoconstriction).

Answer 13

Noradrenaline released and bind to alpha1 adrenoceptors. Phospholipase C activates PIP2 which then produces IP3 and DAG. These will increase calcium and cause contraction.

Question 14

How do bronchiolar smooth muscles contract?

Answer 14

Parasympathetically acetylcholine is released. ACh will bind to M3 which will then go the same signalling pathway by producing IP3 and DAG. This causes bronchoconstriction.

Question 15

Briefly outline modulation of neurotransmitter release.

Answer 15

In both the central and peripheral nervous system neurotransmitter release is often modulated by presynaptic GPCRs.
Morphine binds to u-opioid receptor. G-protein binds and GDP is exchanged for GTP on the alpha I subunit. The beta/gamma subunits dissociate and they will be the ones that inhibit a VOCC channel.