Receptor Families Flashcards
What is a receptor
What does it do
- A receptor is a bifunctional molecule (principal drug target)
- It recognises ligands which reversibly bind to a site and the combination of ligand with receptor triggers a response
What are the 4 receptor superfamilies
- Ion channels
- G-protein-coupled receptors (metabotropic receptors)
- Kinase-linked receptors
- Steroid receptors (IC receptors)
What are GPCRs also known as
Metabotropic receptors
What are steroid receptors also known as
IC receptors
What do VG Ca2+ channels in the heart and BVs influence
Heart rhythm and constriction of BVs
In terms of drugs, what are VG Ca2+ channels a target for (2 points)
- Anti-dysrhythmics (verapamil)
- Anti-hypertensives (amlodipine)
What blocks VG Na+ channels
Local anaesthetics
What is another name for ligand-gated ion channels
Ionotropic receptors
What is a ligand
What happens when a ligand binds to its site on the receptor
Give an example
- A ligand is a small molecule that binds to a receptor
- It causes conformational change, opening the channel and allowing ions to flow through
- Nicotinic receptors to which the endogenous ligand ACh binds
How are ligand gated ion channels activated
By binding of chemical ligand to a site on the channel molecule
Give an example of a ligand-gated ion channel
Explain how it works
Nicotinic ACh receptor
- Nicotine binds and activates the receptor
- Allows Na+ and Ca2+ into the cell
- Stimulant in CNS causes enhanced NT release
- Also causes release of adrenaline from adrenal gland - fight or flight response
What is nicotine in terms of the ACh receptor
A drug that is an exogenous ligand for the ACh receptor
(ACh is the naturally occuring endogenous ligand for this receptor)
Where does the endogenous ligand ACh bind to the nicotinic receptors
What happens as a result
- ACh binds to a site on the alpha subunits opening the channel and allowing Na+ ions to pass through the membrane
Define diazepam
MOA of diazepam
- a benzodiazepine receptor agonist
What is the most abundant class of receptors
What are they also known as
G-protein-coupled receptors
Metabotropic receptors
What is the structure of GPCRs/metabotropic receptors
7 transmembrane helices (heptahelical), with EC domain usually containing the ligand-binding region
What do GPCRs/MRs possess
IC regions that activate G protein signalling molecules (as they bind the guanine nucleotides GTP and GDP)
What do GPCRs/MRs do
Activate the production of 2nd messengers (cAMP, diacylglycerol/DAG and inositol-1, 4, 5-triphosphate/IP3)
Give an example of a GPCR/MR
Beta-adrenoceptors: adrenaline/noradrenaline is endogenous ligand (3 subtypes - B1, B2 and B3)
What is the effect of activation of GPCRs
Phosphorylation of proteins - on/off
What happens when beta-adrenoceptors in the heart are activated
- Phosphorylates VG Ca2+ channels
- Causes the channel to open & Ca2+ comes into the cell
- Contracts heart muscle
- Beta blockers prevent this effect
What do beta blockers do
Prevent activation of beta adrenoceptors in the heart => no phosphorylation of VG Ca2+ channels and Ca2+ does not come into the cell
What are G proteins composed of
What does the G protein act as
3 subunits - α, β, γ (heterotrimeric)
G protein acts as the interface between the receptor and the enzymes and/or ion channels that are ultimate targets of GPCRs
Where is there a binding site for GDP/GTP
What happens when it is occupied by GTP
There is a binding site for GDP/GTP on the α subunit
When this is occupied by GTP, the α subunit separates from the other subunits => inactive when GDP is bound
G protein coupled receptor structure
The series of events once the ligand binds to the G protein coupled receptor
* G protein has an affinity for GDP when not associated with the receptor
* Effector proteins are embedded in the membrane or IC
- Ligand binds
- G protein association - exchange of GDP for GTP on a subunit
- α subunit dissociates and interacts with effector molecule
- Effector molecule activates secondary messengers
- Return to resting state following activation of effector molecule
Name the endogenous ligands of the GPC B2 receptor
Adrenaline & noradrenaline
What are kinase-linked receptors also known as
How many membranes do they span
How do they cause an effect within the cell
What are these receptors involved in
Give an example
- Receptors with enzymatic cytosolic domains
- Single membrane spanning proteins
- Cause an effect within the cell by adding or removing phosphate groups to or from specific AA residues
- Many of these receptors are involved in growth and differentiation
- e.g. insulin receptors (a member of the tyrosine kinases, the largest group)
What must tyrosine kinases do in order to produce their effect
They must associate & form a dimer
Within the action of tyrosine kinases, what happens once a dimer is formed
Phosphorylation of tyrosine residues on effector proteins
Explain how insulin is an example of a tyrosine kinase
- Promotes uptake of glucose from blood into cells for storage (e.g. as glycogen in liver)
- Phosphorylates and activates enzymes that synthesise glycogen, and inactivates enzymes that break down glycogen to glucose
What are NUCLEAR receptors also known as
IC receptors
What is the criteria for the ligand of nuclear/IC receptors
Must be lipid soluble in order to penetrate the membrane
Inactive forms of nuclear/IC receptors that are present in the cytosol or nucleus are associated with…
Transcription regulatory factors
What happens to nuclear/IC receptors once the ligand binds
What does it affect
Give an example
- Migrate to nucleus when the ligand binds
- Affects DNA, altering gene transcription and thus translation of RNA into protein
- e.g. steroid receptors
Explain the steps in the MOA of nuclear/IC receptors
- Ligand enters cell
- Ligand binds
- Ligand-receptor complex enters nucleus, dimerises and binds to DNA and thus altering cellular protein expression
Transcription =
DNA makes RNA
Translation =
RNA makes protein
What effect do steroids have on transcription
give an example
what is the response time
- Activate or inhibit transcription
- e.g. glucocorticoids inhibit transcription of gene for cyclo-oxygenase-2 (COX-2)
- Anti-inflammatory
- Slow response because of time to make or destroy proteins
Receptor summary
What are other drug targets besides receptors
- Ion channels
- Enzymes
- Transporters
