Lecture 10 Flashcards
G Protein-Coupled Receptors
What are the different types of cell-surface receptors?
Receptors with intrinsic enzyme activity, Receptors linked to protein kinases, Receptors coupled to target proteins via a G protein (GPCRs), Intracellular receptors, Ion channel receptors
Why are GPCRs important?
They are the largest class of cell-surface receptors. In August 2024, there were 4483 GPCR genes in the human genome, but only 1447 were confirmed. 60% of all drugs target GPCR pathways.
What is the structure of a GPCR?
Extracellular domains: E1 and loops E2-E4 (for ligand binding), Transmembrane domains: TM1-TM7 (form a ligand-binding cavity), Cytosolic domains: C1-C3 loops & C4 tail (with a lipid anchor)
How do ligands bind to GPCRs?
Small ligands bind inside the transmembrane cavity. Large ligands (peptides, proteins) bind to extracellular loops or the N-terminus. Binding causes TM helices to twist, triggering activation.
How does GPCR activation lead to G-protein activation?
Inactive G-protein: Gα is bound to GDP and forms a trimer with Gβ and Gγ. Ligand binding changes receptor shape. GDP is replaced with GTP on Gα, activating the protein. Gα-GTP separates from Gβγ, activating intracellular targets.
How is GPCR signaling turned off?
Gα has intrinsic GTPase activity, converting GTP → GDP, inactivating itself. Gα-GDP reassociates with Gβγ, returning to the resting state.
What is GPCR desensitization?
GPCR kinase (GRK) phosphorylates the active receptor. Arrestin binds to the phosphorylated GPCR, preventing further activation.
What are the major types of heterotrimeric G-proteins and their functions?
G_s: Stimulates adenylate cyclase → ↑cAMP (Epinephrine, glucagon), G_i: Inhibits adenylate cyclase → ↓cAMP (Adenosine, prostaglandins), G_t: Stimulates cGMP phosphodiesterase (Photons - vision), G_q: Activates phospholipase C → ↑IP₃, DAG (Vasopressin, bombesin), G₁₂: Activates ion channels (Na⁺/H⁺ exchange) (Thrombin)
How does GPCR signaling regulate the fight-or-flight response?
Epinephrine binds β-adrenergic receptors (GPCRs), activating G_s. Adenylate cyclase is activated, increasing cAMP. cAMP activates PKA, leading to increased heart rate (cardiac muscle contraction) and glycogen breakdown (energy release).
How does cholera toxin affect GPCR signaling?
CTxA1 ADP-ribosylates Gα_s, locking it permanently ON. cAMP levels increase 100x, overstimulating CFTR channels. This causes massive ion & water efflux, leading to severe diarrhea.
