GPCR Flashcards
What are the structural components of GPCR?
- 7 transmembrane alpha helices
- amino end and ligand binding site at extracellular site
- carboxyl end at intracellular site with -OH resides
- G protein
What is duration of the onset of action?
Fast due to signal ampification
Which receptor does it bind to?
Formoterol
β2 agonist (Gαs)
- bronchodialator to treat asthma
Which receptor does it bind to?
Phenylephrine
α1 agonist (Gαq)
- treats nasal congestion by vasoconstriction, reduce mucus accumulation
Which receptor does it bind to?
Chlonidine
α2 partial agonist (Gαi)
- treats hypertension via feedback inhibition to reduce vasoconstriction
Which receptor does it bind to?
Atropine
non-selective muscarinic (ACh receptor) antagonist (Gαq, Gαi)
M1 - Gαq
M2 - Gαi
M3 - Gαq
Which receptor does it bind to?
Propranolol
non-selective β antagonist (Gαs)
- treats hypertension via inhibiting β1 by reducing cardiac output
- glaucoma via β2 by inhibiting relaxation of cilliary muscles
Whihc receptor does it bind to?
Cetrizine
H1 inverse-agonist (Gαq)
- binds to and stabalises inactive H1 receptor, prevents activation of Gαq
- anti-allergenic
By which pathway
MOA of Gαs
Adenylyl cyclase pathway
- ligand binds to GPCR
- activation of Gαs
- activates adenylyl cyclase
- converts ATP -> cAMP (cAMP -> AMP by PDE)
- cAMP -> PKA
- PKA -> activate effectors (enzymes, transporters) & CREB
- CREB -> stimulate gene expression
- CREB: cAMP response element binding protein
By which pathway
MOA of Gαi
Adenylyl cyclase pathway
- Gαi activated by ligand binding to GPCR
- Gαi inhibits activation of AC
- less conversion of ATP -> cAMP by AC
- less cAMP -> AMP (by PDE) and PKA
- less PKA to activate CREB -> reduced gene expression
- less PKA to activate downstream effectors (enzymes, transporters)
CREB: cAMP response element binding protein
what is the pathway
MOA of Gαq
inositolphosphatidyl pathway
- Gαq is activated by ligand binding to GPCR
- Gαq activates PLCβ and transporters to import Ca²⁺
- PLCβ converts PIP2 -> IP3 and DAG
- IP3 stimulates ER to release Ca²⁺
- Ca²⁺ binds to calmodulin for downstream signalling effects
- Ca²⁺ -calmodulin activates NOS which produces NO (promotes vasodilation, neurotransmission, immune response)
- DAG -> PKC
- PKC -> PLA2 (converts phospholipids into AA), stimulate TFs (c-FOS & c-JUN to increase gene expression), stimulate downstream signalling effects
NOS: nitric oxide synthase
PLCβ: phospholipase Cβ
IP3: inositol triphosphate
PIP2: phosphatidylinositol bisphosphate
DAG: diacylglycerol
Which pathway?
MOA of Gαt
Rhodopsin photoreceptor signalling pathway
- photon binds to rhodopsin
- Gαt activated
- stimulates cGMP-PDE (PDE6) effector
- PDE6 converts cGMP -> GMP
- decrease in cGMP closes Na/Ca channel causing hyperpolarization due to lack of inward flow of + charges
- brain signals activation of AC
- AC increases cGMP level to open Na/Ca channels
- opening and closing cycle repeats
AC: adenylyl cyclase
How are activated G proteins deactivated?
GTPase cleaves phosphate group on G protein. G protein recycled back into inactive heterotrimeric G protein.
alpha, beta and gamma
modification to GPCR
How to prevent the activation of G proteins?
How can the GPCR be recycled?
Phosphorylating the -OH groups at the carboxyl end of the GPCR. phosphorylated site allows binding of β-Arr. Prevents the binding and activation of G protein.
- internalising GPCR into endosome containing phosphatases
- removes phosphate groups
- GPCR recycled back at CSM
2 ways of receptor regulation.
A. ligand removal (reuptake or degradation)
B. Desensitization (only for agonist):
1. uncoupling ligand from GPCR
2. internalisation of GPCR
3. downregulation (reduce synthesis/degradation)
because antagonist does not elicit direct respose
