The major physiological stimuli of aldosterone secretion are angiotensin II (AII) and extracellular K(+), whereas cortisol production is primarily regulated by corticotropin (ACTH) in fasciculata cells. AII triggers Ca(2+) release from internal stores that is followed by store-operated and voltage-dependent Ca(2+) entry, whereas K(+)-evoked depolarization activates voltage-dependent Ca(2+) channels. ACTH acts primarily through the formation of cAMP and subsequent protein phosphorylation by protein kinase A. Both Ca(2+) and cAMP facilitate the transfer of cholesterol to mitochondrial inner membrane. The cytosolic Ca(2+) signal is transferred into the mitochondrial matrix and enhances pyridine nucleotide reduction. Increased formation of NADH results in increased ATP production, whereas that of NADPH supports steroid production. In reality, the control of adrenocortical function is a lot more sophisticated with second messengers crosstalking and mutually modifying each other's pathways. Cytosolic Ca(2+) and cGMP are both capable of modifying cAMP metabolism, while cAMP may enhance Ca(2+) release and voltage-activated Ca(2+) channel activity. Besides, mitochondrial Ca(2+) signal brings about cAMP formation within the organelle and this further enhances aldosterone production. Maintained aldosterone and cortisol secretion are optimized by the concurrent actions of Ca(2+) and cAMP, as exemplified by the apparent synergism of Ca(2+) influx (inducing cAMP formation) and Ca(2+) release during response to AII. Thus, cross-actions of parallel signal transducing pathways are not mere intracellular curiosities but rather substantial phenomena, which fine-tune the biological response. Our review focuses on these functionally relevant interactions between the Ca(2+) and the cyclic nucleotide signal transducing pathways hitherto described in the adrenal cortex.
Keywords: ACTH; Ca2+ signal; aldosterone; angiotensin II; cAMP; cortisol; mitochondria; potassium ion.