Drug Targets - G-protein coupled receptors (GPCR) Flashcards
G-protein coupled receptor (GPCR)
In the genome (~800 proteins), it is the most common receptor
-most neurotransmitters, hormones have one or more GPCR receptors
~30 % of commercial drugs target GPCRs
Where is receptor located?
in cell membrane
G proteins is COUPLED to ______
receptor
G proteins =
alffa
beta
gama
When ligand binds to receptor;
activates the GDP thats attached
dissociation of G protein; alpha separates from beta and gama - therapeutic response
receptor signalling effects what 3 things
specificity, sensitivity & fidelity
How many trans membranes are there?
7 trans-membrane spanning domains (key feature of G-protein receptors)
Intracellular C terminus
3 ECL (extracellular loop), 3 ICL (intracellular loops)
Extracellular N terminus - different amino acid sequence
Most GPCRs share ________ structure but DISTINCT aminoacid sequences (specificity for ligand binding)
SIMILAR
FSH - type of GPCR (binds extracellular)
FSH helps manage the menstrual cycle and stimulates the ovaries to produce eggs
What is a G-protein?
guanine nucleotides bound proteins
Heterotrimeric proteins (different three subtypes)
Located intracellular, lipid anchors helps to mobilise in intracellular membrane
G alpha (Ga)- Binds to guanosine diphosphate (GDP) or guanosine triphosphate (GTP)
G beta + G gamma - mostly form a dimer
steps of the G-protein cycle
- When resting/inactive, Ga binds GDP and forms a complex with Gbg
- Upon ligand binding, GPCRs gets activated and catalyse exchange of GDP for GTP on Ga
- Ga-GTP and Gbg dissociate from each other and activate effector proteins
- The GTPase activity of Ga converts bound GTP back to GDP
- Ga-GDP reassociates with Gbg, returns to inactive state
GPCR- Effectors
The specific GPCRs select G proteins containing one class of Ga subunits to generate a specific response: stimulatory or inhibitory
1) Ga subunits type
2) Effector
3) 2nd messenger
4) Function
Gsa > Adenylyl cyclase > cAMP > Stimulatory
(neurotransmitter release, smooth muscle relaxation)
Gia > Adenylyl cyclase > cAMP > Inhibitory
(neurotransmitter release, smooth muscle contraction)
Gqa > Phospholipase C > calcium > Stimulatory
(neurotransmitter release, smooth muscle contraction)
example of Ga subunits=
Gbg subunits have effectors as well – e.g. potassium ion channels
GPCR - activate what subunits?
Neurotransmitters/hormones can activate multiple subunits of Ga coupled receptors
