The desensitization of beta-adrenoceptors following prolonged agonist exposure is primarily mediated by which intracellular mechanism?

• A Downregulation of adenylyl cyclase catalytic subunit expression
• B Competitive displacement of Gs protein from receptor coupling domain
• C Receptor internalization via clathrin-coated pits after phosphorylation by GRK2 and beta-arrestin recruitment ✓
• D Upregulation of phosphodiesterase-4 to degrade accumulated cAMP

Explanation

Beta-adrenoceptor desensitization proceeds in two phases: rapid uncoupling via G-protein receptor kinase 2 (GRK2, also called beta-ARK1) phosphorylation of the agonist-occupied receptor, followed by beta-arrestin binding which sterically blocks Gs coupling and targets the receptor for internalization through clathrin-coated pits. This mechanism explains tachyphylaxis with chronic beta-agonist use in asthma. The other options describe downstream effects that may follow but are not the primary desensitization mechanism.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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