Topic 1: receptor diversity

Question 1

What structures do all GPCRs share?

Answer 1

All have
7-TMD
Extracellular N- terminal
Intracellular C- terminal
and single polypeptide chain

Question 2

what are the three families of GPCRs?

Answer 2

Family A ( Rhodopsin like)
Family B (Glucagon -like)
Family C (metabotropic glutamate like)

Question 3

What happens when and ligand binds to a receptor?

Answer 3

the receptor is fluid, it is constantly moving a ligand binding leads to the stabilisation of the receptor in a particular conformation that set off down steam signalling.

Question 4

Where do ligands bind in family A GPCRs?

Answer 4

specific amino acid residues in the TM regions contribute to the ligand binding site.

Question 5

how many points of contact are there in faimly B GPCRs with their ligands?

Answer 5

two

Question 6

What is a RAMP protein?

Answer 6

A receptor activity-modifying protein

Question 7

what do RAMP proteins bind to

Answer 7

Some family B GPCRs bind to RAMP, and allow for interaction with another ligand for example the CRL (calcitonin receptor-like protein) binds to RAMP1 and CGRP (calcitonin gene-related peptide) with high affinity.
also different RAMPs can change what agonist binds to the receptor.

Question 8

what evidence is there that GPCRs exist in a oligomeric structures?

Answer 8

High molecualr weights on tests

Question 9

What receptor is a obligate hetromer? what is its mechism of action?

Answer 9

the family C GABAb receptor - both B1 and B2 receptors are needed to generate a functional receptor.
the GABA B1 caointains a ER retention signal and needs to coassemble with B2 to permit passge into the plasma membrane.
the B1 subunit also binds to the ligand, but the B2 binds to the G-protien but there are also interactions where this is swapped.

Question 10

what is an orphan GPCR ?

Answer 10

A GPCR with no known endogenous ligand,
they could be undiscovered ligands or may dimerise with other GPCRs to have and effect.

Question 11

what is a NME (novel molecular entity) ?

Answer 11

systesied chemicals that interact with a receptor

Question 12

what is an allosteric modulator?

Answer 12

a molecule that acts at a non orthosteric site

Question 13

What is a allosteric ligand?

Answer 13

a ligand that does not bind at the orthosteric site.

Question 14

what is a negative allosteric modulator? give an example.

Answer 14

binds alostericly and hence non-competitively to a receptor and reduces it ability to be activated. and example would be MT7 which binds to mAChR and decreases the ability of the receptor to be activated by ACh.

Question 15

What are the receptor superfamilies?

Answer 15

GPCR
inotropic glutatamate
enzymelinked RTKs
nuclear receptors

Question 16

what is the machoism of action for RTKs?

Answer 16

single transmembrane spanning polypeptides that dimerise on ligand binding - C terminal of each monomer phosphorylates the other monomer of the dimer pair (autophosphorylation) on specific tyrosine residues to form phospo-tyrosine docingsites for proteins containing SH2 (SRc-homology-2) domains.
this allows for RTK to act as scaffolding for intracellular signalling pathways.

Question 17

what therapeutic uses RTKs?

Answer 17

HER2 (epidermal growth factor) is a RTK related to EGFR, which has no ligand- it is belived to dimerise with with EGFR to become active and is over expersses in breast cancer- hence there are approaes to block HER2 signalling

Question 18

What are two types of nuclear receptors?

Answer 18

Class 1 and class 2

Question 19

what is the mechanism of action for nuclear receptors?

Answer 19

lipophilic ligand permeates PM to reach receptor, binds the receptor, receptor undergoes ligand dependent and release form cytoplasmic sequestration, receptor dimerrises adn reaches nucelus, receptor binds DNA adn recrequtes coactivators to increaser transceriotion. for specific genges

Question 20

what is the machoism of action for lidocaine?

Answer 20

Lockeds the Na+ channel when it is in ether the opn or incactiavted state- channel needs to be open to work.
it is a use dependent block

Question 21

what is a use dependent block

Answer 21

the more a ion channel is open ther more the channels will be blocked- hydrophomic pathwyas do not have this.

Question 22

why can lidocaine be used as an antidisrhuthmic drug?

Answer 22

can reduce tacicardia as it can bind and block the Na+ channels leading to a reduction in the speed of the riseing pahse of the ventricualr action potential.

Question 23

why can lamotrignine be used as an anti-epileptic ?

Answer 23

it is an intracellular Na+ open channel blocker, so will reduce the upward spike of an AP hence more reduce spiklets or prematiure APs, and is use dependent.

Question 24

how many states do calcium ion channels have?

Answer 24

three,
resting
open
inactivated
drugs can preferentially bund to different states.

Question 25

what are the two classes of Ca2+ blockers?

Answer 25

Phnylalkylamines -charged and effective in the heart
Dihydropyridines- neurtral and effctivie in vascular smooth muscle.

Question 26

when state can phenylalkyamines bind to?

Answer 26

only in the open state- therefore strictly use dependent- sueful in preventing disarrthmias

Question 27

what state can dihydropyridines block?

Answer 27

open or inactivated - therefore block is use and voltage dependent
as vasular smooth muscle tone is controlled by depolarisation it is usfull here - hypertention
selective affinity for smoth muscle in the inactivated state will have some effcts on heart but minimal -nifedipine.

Question 28

how can Ca2+ channel blockers be used to treat epilepsy?

Answer 28

Gabapentin- binds to A2 delta
modualtes ca2+ influx and hence slows neurotransmitter relase.