Topic 1: receptor diversity Flashcards
What structures do all GPCRs share?
All have
7-TMD
Extracellular N- terminal
Intracellular C- terminal
and single polypeptide chain
what are the three families of GPCRs?
Family A ( Rhodopsin like)
Family B (Glucagon -like)
Family C (metabotropic glutamate like)
What happens when and ligand binds to a receptor?
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.
Where do ligands bind in family A GPCRs?
specific amino acid residues in the TM regions contribute to the ligand binding site.
how many points of contact are there in faimly B GPCRs with their ligands?
two
What is a RAMP protein?
A receptor activity-modifying protein
what do RAMP proteins bind to
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.
what evidence is there that GPCRs exist in a oligomeric structures?
High molecualr weights on tests
What receptor is a obligate hetromer? what is its mechism of action?
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.
what is an orphan GPCR ?
A GPCR with no known endogenous ligand,
they could be undiscovered ligands or may dimerise with other GPCRs to have and effect.
what is a NME (novel molecular entity) ?
systesied chemicals that interact with a receptor
what is an allosteric modulator?
a molecule that acts at a non orthosteric site
What is a allosteric ligand?
a ligand that does not bind at the orthosteric site.
what is a negative allosteric modulator? give an example.
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.
What are the receptor superfamilies?
GPCR
inotropic glutatamate
enzymelinked RTKs
nuclear receptors
what is the machoism of action for RTKs?
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.
what therapeutic uses RTKs?
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
What are two types of nuclear receptors?
Class 1 and class 2
what is the mechanism of action for nuclear receptors?
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
what is the machoism of action for lidocaine?
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
what is a use dependent block
the more a ion channel is open ther more the channels will be blocked- hydrophomic pathwyas do not have this.
why can lidocaine be used as an antidisrhuthmic drug?
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.
why can lamotrignine be used as an anti-epileptic ?
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.
how many states do calcium ion channels have?
three,
resting
open
inactivated
drugs can preferentially bund to different states.
what are the two classes of Ca2+ blockers?
Phnylalkylamines -charged and effective in the heart
Dihydropyridines- neurtral and effctivie in vascular smooth muscle.
when state can phenylalkyamines bind to?
only in the open state- therefore strictly use dependent- sueful in preventing disarrthmias
what state can dihydropyridines block?
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.
how can Ca2+ channel blockers be used to treat epilepsy?
Gabapentin- binds to A2 delta
modualtes ca2+ influx and hence slows neurotransmitter relase.
