The calcium-sensing receptor (CaSR) on parathyroid chief cells is a Gq-coupled GPCR. When plasma Ca²⁺ rises, CaSR activation inhibits PTH secretion. The intracellular signaling cascade by which CaSR activation suppresses PTH exocytosis is:

• A CaSR → Gαs → increased cAMP → PKA → phosphorylates and activates secretory vesicle fusion machinery
• B CaSR → β-arrestin → MAPK activation → transcriptional suppression of PTH gene within minutes
• C CaSR activates voltage-gated K⁺ channels causing hyperpolarization, which closes voltage-gated Ca²⁺ channels and stops exocytosis
• D CaSR → Gαq → PLCβ → IP₃ → Ca²⁺ release → CaMKII activation → also Gαi → reduced cAMP; collectively these reduce PTH granule exocytosis ✓

Explanation

CaSR is primarily Gαq-coupled (PLC→IP₃→Ca²⁺→CaMKII) but also couples to Gαi (reducing cAMP). The rise in intracellular Ca²⁺ from IP₃-mediated ER release, combined with decreased cAMP (inhibiting PKA), suppresses PTH exocytosis. Paradoxically, CaSR raises intracellular Ca²⁺ even as it reduces exocytosis — this is because the signaling Ca²⁺ rise (from ER) does not adequately compensate for the reduced cAMP-PKA signaling. Cinacalcet is a CaSR-positive allosteric modulator (calcimimetic) used in secondary hyperparathyroidism; it sensitizes CaSR to plasma Ca²⁺.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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