Flashcards in MR 7 Deck (12)
Briefly discuss diseases associated with signal transduction.
These either lead to gain of function (ligand not needed) or loss of function.
Retinitis pigmentosa - loss of function
Familial male precocious puberty - gain of function
Nephrogenic diabetes insipidus - loss of function
Describe the structure of GPCRs
-7 transmembrane proteins
-single polypeptide chain (300-1200aa)
-they are heterotrimers but function as dimers.
What is the configuration of GPCRs in their basal state?
Alpha subunit is bound to BY complex, with GDP bound to the alpha. (It is the association of GDP with the alpha that increases the affinity for the BY of the A subunit).
Describe the conformational change of the GPCR upon ligand binding, and the fate of the subunits.
-GDP exchanged for GTP
-affinity for BY of the A decreases so the two dissociate
-BY still remain attached to each other - functionally they are one.
- A and BY then go on and interact with their respective effector molecules.
Explain how the length of activation of GPCRs is governed.
-A and BY dissociate when GTP bound
-A subunit has intrinsic GTPase which hydrolyses the GTP
-when GTPase hydrolyses GTP into GDP, the affinity for BY increases
-A and BY subunits bind with each other again and then the receptor inactivated.
How does the termination of action of the GPCR occur?
Via intrinsic GTPase activity of the A subunit.
Describe what happens after the activation of Adenylyl cyclase
When Gs is actviated, there is an increase in Adenylyl cyclase.
AC hydrolyses ATP to cAMP.
cAMP interacts with PKA (dependent on cAMP)
PKA phosphorylates other proteins that have stimulatory or inhibitory effects.
AC can also be inhibited, when the receptor Gi is activated.
Describe what happens when Gq is activated.
-you see an increase in calcium
-increase in Phospholipase C
- PLC hydrolyses PIP2, a membrane phospholipid
- PIP2 hydrolysed into IP3 and DAG
-IP3 binds to its receptors on the SER, causing release of calcium
-DAG interacts with PKCs.
Describe the cellular sequence of events when Noradrenaline binds to B1 adrenoreceptors.
-B1 = Gs - linked to AC
- AC causes increase in cAMP and hence PKA
- PKA phosphorylates Ca channels
- increase in Ca
- inotropic effect in the heart.
Describe the effect of noradrenaline activation of A1-adrenoreceptors
-linked to Gq
- Gq= PLC linked
- hydrolysis of PIP2 into DAG and IP3
- IP3 binds to SER receptors causing release of calcium.
Describe what happens with the activation of M2 receptors in the SAN
- coupled to GI
- decrease AC and hence decrease PKA
- increases the open probability of K+ channels
- more K+ efflux so hyperpolarisation and hence slower heart beat.
- negative chronotropic effect.