PTH increases serum calcium partly by stimulating 1α-hydroxylase in the kidney. Which molecular mechanism mediates PTH's action on proximal tubular cells to activate 1α-hydroxylase?

• A PTH activates a JAK2-STAT3 pathway in proximal tubular cells, directly transactivating the CYP27B1 promoter
• B PTH-induced hypocalcaemia directly activates the calcium-sensing receptor (CaSR) in reverse, upregulating CYP27B1 via Gi inhibition
• C PTH1R (Gs-coupled GPCR) activates cAMP-PKA pathway, phosphorylating and upregulating CYP27B1 (1α-hydroxylase) gene expression; additionally, PKC from Gq pathway and reduced FGF23 signalling (from hypophosphataemia) synergise ✓
• D PTH signals via mTOR pathway in mitochondria to allosterically activate the CYP27B1 enzyme without changing its transcription

Explanation

PTH binds PTH1R (a Gs/Gq-coupled GPCR) in the proximal tubular cells of the kidney. Gs activation elevates cAMP and activates PKA, which phosphorylates transcription factors (including CREB) that upregulate CYP27B1 (25-hydroxyvitamin D-1α-hydroxylase) expression, converting 25(OH)D to 1,25(OH)2D (calcitriol). The Gq-PKC pathway also contributes. Concurrently, PTH-induced hypophosphataemia (by reducing renal phosphate reabsorption) further stimulates CYP27B1, as phosphate itself suppresses 1α-hydroxylase; and FGF23 (from bone, stimulated by high phosphate and calcitriol) inhibits CYP27B1 — so FGF23 reduction synergises with PTH. Calcitriol then acts on the intestine to increase Ca2+/phosphate absorption.

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

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