G-protein Coupled Receptors Flashcards
When an agonist binds to its receptor, what is formed?
A drug-receptor (D-R) complex
Triggers a biological response, what is this process?
Signal transduction
List the 3 stages of the receptor signalling process
- Signal reception (agonist drug binds to & activates receptor)
- Signal transduction (produces 2nd messengers inside cell)
- Cellular response (biological response signal triggered)
List the 4 major signal transduction pathways
- Activation of receptor-ion channels (Ligand-gated)
- Activation of second messenger pathways (GPCRs)
- Activation of enzyme-linked receptors (kinase-linked)
- Direct activation of gene transcription via intracellular receptors
What is the timescale for each receptor superfamily?
- Ligand-gated: milliseconds (nicotinic)
- GPCRs: seconds (muscarinic)
- Kinase-linked: hours (cytokine)
- Nuclear: hours (oestrogen)
What do GPCRs convert?
Convert extracellular signals into intracellular responses
What structure do GPCRs share?
7-TM a-helices
What does a GPCR consist of?
- Extracellular region: N terminus & 3 extracellular loops (ECL1-3)
- TM region: 7TM a-helices
- Intracellular region: ICL 1-3
What are heterotrimeric G-proteins composed of?
a, B and y
Two subunits: a subunit (Ga) and a tightly associated By complex
What 2 domains is the Ga subunit composed of?
- Ras-like domain
- a-helical domain
What is located between the 2 domains of the Ga?
A nucleotide-binding pocket
How are G-proteins classified?
Based on their Ga subunits
List the 4 Ga families
1) Gas - stimulate adenylate cyclase
2) Gai - inhibit adenylate cyclase
3) Gaq/11 - stimulate phospholipase
4) Ga12/13 - activate the Rho family of GTPases
Most Ga proteins mediate GPCR signalling by regulating the levels of intracellular regulatory molecules called ______
second messengers
Adenylyl cyclase (AC) converts _____ to _____
____ stimulates this activation of AC
ATP
cAMP
Gas-GTP
Increased cAMP level leads to activation of ____
protein kinase A (PKA)
Gaq/11-GTP activates PLCB in ______
cell membrane
Activated phospholipase C-B (PLCB) generate 2nd messengers
__________
__________
Inositol triphosphate (IP3) Diacylglycerol (DAG)
IP3 diffuses through cytosol and releases _____ from ER
Ca2+
DAG activates_______
protein kinase C
GB & Gy form ______
obligate functional heterodimer
Temporal & spatial signalling of activated GPCRs is controlled by _____ & _______
Desensitisation
Internalisation
What 2 major intracellular actors does this trafficking require?
- G-protein coupled receptor kinases (GRKs)
- B-arrestins (cytoplasmic adaptor proteins)
What do B-arrestins facilitate?
Receptor internalisation
What are the 3 possible fates when GPCRs are trafficked to endosomes?
- May be dephosphorylated by phosphates & recycle back to cell surface for future signalling
- May be sorted to lysosomes for degradation
- May activate B-arrestin & G-protein independent signalling
What do B-arrestins couple the phorphorylated GPCRs to?
clathrin-coated pits
