A patient undergoes surgical stress. Within 30 minutes, serum cortisol rises from 12 to 38 μg/dL. The acute cortisol secretion in response to ACTH stimulation occurs by which cellular mechanism?
- A ACTH binds MC2R → cAMP → PKA → StAR protein phosphorylation → cholesterol transport from outer to inner mitochondrial membrane → rapid steroidogenesis (rate-limiting step) ✓
- B ACTH binds MC2R → IP3 → intracellular Ca²⁺ release → calmodulin kinase II activation → cortisol exocytosis from pre-formed granules
- C ACTH activates tyrosine kinase receptor → PI3K/Akt pathway → direct phosphorylation of CYP11A1 to increase cortisol synthesis
- D ACTH increases intracellular LDL uptake by upregulating LDL receptors, providing additional cholesterol substrate for immediate steroidogenesis
Explanation
ACTH binds the melanocortin 2 receptor (MC2R, a Gs-coupled GPCR) on adrenocortical zona fasciculata cells, activating adenylyl cyclase and raising cAMP. PKA is activated and phosphorylates Steroidogenic Acute Regulatory (StAR) protein, which transports cholesterol from the outer to the inner mitochondrial membrane — the acute rate-limiting step of steroidogenesis. CYP11A1 (P450scc) on the inner membrane then cleaves the cholesterol side chain to pregnenolone, initiating the cortisol biosynthetic cascade. This explains the acute cortisol surge within minutes. Option B incorrectly describes the mechanism (cortisol is not stored in granules; it is synthesized de novo and diffuses out). Option C describes a receptor tyrosine kinase pathway (growth factor signaling), not applicable to ACTH. Option D is a chronic (not acute) adaptive mechanism.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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