Properties and function of different receptor types and their associated cellular mechanisms Flashcards
receptor
what ois it?
what does it do?
4 key features of receptor?
Recognise and bind drugs – endogenous or ‘given’ chemicals
Provide communication between extracellular and intracellular environments to produce biological response
Tissue selectivity
Chemical selectivity
Extracellular/intracellular communication
Amplification
different types of receptors
4 types
give examples for all of them
Receptors
Associated with the plasma membrane
(some are found inside cell – see intracellular/nuclear receptor later in lecture)
Communication between outside and inside of cell
Enzymes
Sildenafil (erectile dysfunction) - blocks PDE-5
Aspirin (analgesic) - blocks COX
Carrier molecules
Diuretics – inhibits Na+/K+/Cl- carriers and Na+ reuptake in kidney
Digoxin - inhibits Na+/K+ ATPase, used atrial fibrillation
Fluoxetine - blocks serotonin uptake, anti-depression
Ion Channels
Local anaesthetics, e.g. lignocaine - ‘plugs’ Na+ channel pore
Anti-hypertensives, e.g. Ca2+ channel blockers
Common property of the receptor family
what kind of proteins?
what does the specific sequence of amino acids affect? (3)
Trans-membrane proteins
It is the specific sequence of amino acids that compose:
Selectivity of drug bound
Type of intracellular pathways activated
Timescale of information transfer (ms to days)
Classification of receptor families: (4)
Ligand-gated receptors
G-protein-coupled receptors
Tyrosine kinase receptors
Intracellular receptors
Ligand-gated receptors
what do nicotinic receptors control?
what do glutamate receptors control?
how many protein subunits make up ligand-gating receptors?
how many transmembrane region in each subunit?
what do the subunits form?
what terminal region does ligand bind? which site?
Nicotinic receptors - controlling skeletal muscle contraction
Glutamate receptor – controlling action potential firing in brain
Ligand-gating receptors composed of five protein subunits
Each subunit has 4 transmembrane region
Subunits form an ion channel
Ligand-binding site on N-terminal region
Extracellular site
Ligand-gated receptors - signal transduction pathway
what happens when ligand binds to receptor?
example of Nic/glutamate and GABA receptors
speed?
Ligand binds to receptor -> Conformation change in subunits -> Ion channel opens -> increase ion flux -> change in cell excitability
e.g. Nic/Glutamate receptor - Na influx - excitation
GABAa receptors – Cl influx – inhibition
This is a very fast response: milliseconds (ms)
G-protein-coupled receptors
example? protein? transmembrane regions? where does ligand bind? where does G-protein bind?
e.g. β-adrenoceptors in heart
1000s of GPCRs, e.g. smell, taste
1 Single protein
7 transmembrane regions
N-terminal - ligand-binding site
C-terminal - G-protein binding region
G-protein-coupled receptors - signal transduction pathway
what happens when ligand binds to receptor?
speed?
Ligand binds to receptor -> Activation of G-proteins Production of intracellular messengers -> cellular function
Slower response than ligand-gated receptors: seconds to minutes
What are G-proteins?
what are they? composed of how many units? what are they?
what do they do?
where do the subunits bind?
Guanine nucleotide (GTP/GDP) binding proteins- composed of 3 subunits, a B Y Couple drug-receptor interaction to cellular response
a - part of G unit
B and Y - tether G protein to plasma membrane
Drug binding effect on G protein
no drug bound effect?
drug bound effect? what induces cellular response?
what stops cellular response? (2) effect of this?
No drug bound – G-protein bound to receptor, GDP is bound to a subunit
Drug binding
Change in receptor conformation so a subunit is now exposed due to change in structure + wants to bind to GTP due to high affinity
Now GTP binds to Ga subunit
Ga subunit dissociates from B Y subunits – induces cellular response via activating other pathways
Drug unbinds therefore change in confirmation again OR Intrinsic Gα subunit GTPase activity – GTP dephosphorylates to GDP
G-protein a B Y subunits re-associate and bind with unbound receptor
G-protein only need low dose drug
why?
Lots more G-proteins than receptors
Lots of a subunits can be stimulated hence there is an amplification as lots of pathways will be activated too
Different G protein a subunits
name 3 examples
name the two main targets
explain why they are the 2 main targets and for which pathways
Different subtypes of a subunits, e.g. Gas, Gai, Gaq
Different a subunits interact with specific targets
Two main targets are adenylate cyclase (AC) and phospholipase C (PLC)
ATP -> (Gas/Gai and AC activity) -> cAMP
PIP2 -> (Gaq and PLC activity) -> DAG + IP3
cAMP, DAG and IP3 are termed intracellular messengers
Gs and Gi –mediated adenylate cyclase pathways
what do they stimulate/inhibit?
what does this change?
Gas stimulate adenylate cyclase so more ATP to cAMP which stimulate more PKA
Gai inhibit adenylate cyclase so less ATP to cAMP which means less PKA stimulated
Change in biological response
Often have opposing actions,
e.g. Gs increases heart rate, Gi inhibits heart rate
Gq-mediated phospholipase C pathway
what will be stimulated? effect of this? (2)
repsonse? example?
Gaq will stimulate PLC so PIP2 will convert into DAG and IP3
DAG will activate PKC
IP3 will bind to IP3 receptor on the SR which will relase ca2+
Increase in cytosolic [Ca2+]
Biological response
e.g. Contraction of smooth muscle in eye, GI tract, blood vessels, airways
Tyrosine kinase receptors
protein? transmembrane domain>
where does ligand bind?
where does effector bind?
Monomer – 1 single protein subunit
1 transmembrane domain
N-teminal extracellular- binds ligand
C-terminal intracellular- bind effector
