GPCR

Question 1

Wha are GPCRs?

Answer 1

Receptor with transmembrane region that passes through membrane 7 times
Intracellular domain contains many hydroxyl groups of serine and threonine

Question 2

What is the GCPR signalling pathway?

Answer 2

1. Signal - odourant, hormone, neurtransmitter, light, drug
   activates GPCR causing a conformational change that enhances G protein interactions
2. Activated receptor dramatically accelerates GDP release from Alpha subunit of G protein, leading to rapid GTP binding, activation, and alpha subunit dissociation from gamma and beta
3. GTP bound alpha subunit stimulates effector (activate or inhibit)

Question 3

What is Formoterol?

Answer 3

b2 adrenoreceptor agonist, which activates Gas subunit
Activation of adenylyl cyclase, converts ATP to cAMP,
which activate cAMP dependent protein kinase (PKA)

either degraded by Phosphodiesterase to 5’AMP
or activates Enzymes, ion channels, or cAMP response element binding protein (CREB) for gene expression

Question 4

What is clodinine?

Answer 4

a2 adrenoreceptor agonist (negative feedback inhibition)
Gai
Inhibit adenylyl cyclase, stop conversion of ATP to cAMP

Inhibition of cAMP dependant protein kinase PKA

Lesser Gene expression and enzymes and ion channel activation

Question 5

What is Phenylephrine?

Answer 5

a1 adrenoreceptor agonist Gaq
Activates Phospholipase C beta

Cleavage of PIP3 to Inositol triphosphate IP3 and Diacylglycerol DG

DG activates Protein Kinase C PKC
PKC activates PLA2 which cleaves phospholipids to form eicosanoids from Arachidonic Acid
PKC also directly modulates ion channels, enzymes, and contractile proteins and gene expression

IP3 regulates calcium release in Endoplasmic Reticulum which also modulate enzymes, ion channels and contractile proteinsq

Question 5

What is Rhodopsin signalling pathway?

Answer 5

Photon binds to Rhodopsin receptor
Rhodopsin activates Gat (transducin)
Gat activates cGMP specific Phosphodiesterase, which decrease cGMP levels
this causes closure of Na/Ca channels
leads to hyperpolarisation which sends a signal to the brain

The decrease in Ca activates guanylyl cyclase
Increase in cGMP leads to reopening of Na/Ca
the cycle restarts

Question 6

What are the differences between Gaq, Gai, Gas?

Answer 6

Gas/Gai/Gat -> ion Channels, Adenylyl cyclase, Src tyrosine kinase, cGMP PDE
Gaq -> Phospolipase Cb

Question 7

How is Signal Amplification achieved?

Answer 7

1. One activated receptor can activate multiple G proteins
2. One effector can make or degrade multiple secondary messenegers

Question 8

How is Receptor activity regulated?

Answer 8

1. Ligand Removal
2. Desensitisation of receptor (Tachyphylaxis, tolerance)
   step 1: uncoupling of Receptor, G protein or effector
   step 2: Internalisation - sequestration, relocalisation, compartmentalisation
   step 3: down regulation - proteolytic degradation, decreased synthesis

Question 9

What are the clinical relevance of Formoterol?

Answer 9

b2 adrenic receptor agonist - Anti-asthma drug

Question 10

What is the clinical relevance of Phenylephrine?

Answer 10

a1 adrenic recptor agonist - Nasal Decongestant

Question 11

What is Homologous desensitisation?

Answer 11

Only effects the receptor involved, arrestin, GRK

Question 12

What is heterologous desensitisation?

Answer 12

Spillover effect of desensitisation of one receptor on another receptor, PKA PKC