g protein coupled receptors

What are the main classes of GPCRs?

• Class A (Rhodopsin-like).

• Class B (Secretin-like).

• Class C (Metabotropic glutamate)

Class A: Rhodopsin-like

• short n terminus

• agonists bind with extracellular loops and transmembrane domains

• e.g., dopamine receptors

Class B: Secretin-like

• larger, globular N-terminus, plays a role in agonist binding

• bind larger peptide hormones

• e.g., glucagon, calcitonin receptors

Class C: Metabotropic glutamate

• very large N-terminal domain binds agonists, form obligatory dimers

• binds small molecules like amino acids

How do GPCRs transmit signals inside the cell?

1. Ligand binds to GPCR.

2. GPCR goes through confirmational change activating heterotrimeric G proteins (α, β, γ subunits).

3. G protein dissociates into Gα and Gβγ subunits, regulating downstream effectors.

What are examples of effector enzymes activated by GPCRs?

• Adenylyl Cyclase: Converts ATP to cyclic AMP (cAMP)

• Phospholipase C: Breaks down PiP2 to produce IP3 and DAG

What are the roles of second messengers in GPCR signaling?

• cAMP: Activates protein kinase A (PKA).

• IP3: Triggers calcium release from the ER.

• DAG: Activates protein kinase C (PKC).

How is GPCR signaling terminated?

GTP hydrolysis by the Gα subunit restores the inactive state.

What is desensitization in GPCR signaling?

A reduction in receptor responsiveness despite continued stimulation

What mechanisms cause GPCR desensitization?

• Phosphorylation: GPCR kinases (GRKs) phosphorylate the receptor, promoting arrestin binding.

• Internalisation: Receptors are removed from the membrane via endocytosis

What is tolerance

A decrease in drug efficacy over time due to prolonged use

What causes GPCR tolerance?

• Receptor downregulation

• Enhanced drug metabolism.

• Adaptation of signalling pathways.