PTH increases serum calcium via multiple mechanisms. In the kidney, PTH acts on the proximal tubule to increase calcitriol synthesis. What is the enzyme activated and via which signaling pathway?

• A PTH → direct activation of 25-hydroxylase (CYP2R1) in the liver to increase 25-OH-vitamin D levels
• B PTH → Gi-coupled PTH1R → reduced cAMP → activation of 1α-hydroxylase via PKC exclusively
• C PTH activates 24-hydroxylase (CYP24A1) in the kidney, converting 25-OH-vitamin D to the active 1,25 form
• D PTH → PTH1R (Gs/Gq-coupled) → cAMP/PKA pathway → phosphorylates and activates 1α-hydroxylase (CYP27B1) in proximal tubule mitochondria, converting 25-OH-vitamin D to 1,25-(OH)₂-vitamin D (calcitriol) ✓

Explanation

PTH binds PTH1 receptor (a Gs/Gq-coupled GPCR) in proximal tubule cells. The Gs-cAMP-PKA pathway is the primary signal activating 1α-hydroxylase (CYP27B1) in the inner mitochondrial membrane. CYP27B1 converts 25-hydroxycholecalciferol (25-OH-D, the major circulating form) to 1,25-dihydroxycholecalciferol (calcitriol, the active form). Calcitriol then increases intestinal Ca²⁺ absorption (via TRPV6/calbindin induction), bone resorption, and renal Ca²⁺ reabsorption. PTH simultaneously suppresses 24-hydroxylase (CYP24A1, which catabolizes calcitriol), ensuring maximal active vitamin D levels. Low phosphate and low Ca²⁺ are independent stimuli for CYP27B1.

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

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