Signaling Interactions in the Adrenal Cortex

Abstract

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 Ca2+ release from internal stores that is followed by store-operated and voltage-dependent Ca2+ entry, whereas K+-evoked depolarization activates voltage-dependent Ca2+ channels. ACTH acts primarily through the formation of cAMP and subsequent protein phosphorylation by protein kinase A. Both Ca2+ and cAMP facilitate the transfer of cholesterol to mitochondrial inner membrane. The cytosolic Ca2+ 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 Ca2+ and cGMP are both capable of modifying cAMP metabolism, while cAMP may enhance Ca2+ release and voltage-activated Ca2+ channel activity. Besides, mitochondrial Ca2+ 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 Ca2+ and cAMP, as exemplified by the apparent synergism of Ca2+ influx (inducing cAMP formation) and Ca2+ 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 Ca2+ and the cyclic nucleotide signal transducing pathways hitherto described in the adrenal cortex.

The Effect of Extracellular Calcium Metabolism on Aldosterone Biosynthesis in Physiological and Pathological Status

“…However, the binding of PTH to PTH receptor also generated inositol 1,4,5-trisphosphate (IP 3 ) following an activation of phosphoinositide-specific phospholipase C (PLC) [47]. Activated IP 3 transiently increased intracellular calcium level, which subsequently activated CaMK [25,52]. In addition, increased cytosolic Ca activates protein kinase C (PKC), which act on protein kinase D (PKD) to activate cAMP response element binding (CREB) stimulating StAR transcription and subsequently increased CYP11B2 expression level [25,37].…”

Aldosterone Synthase Gene (CYP11B2) Polymorphisms and Enhanced Cardiovascular Risk

“…It is mediated by acting on angiotensin 1 (AT1) receptor, a specific G-protein-coupled receptor that activates phospholipase C. Once activated, phospholipase C hydrolyses phosphatidyl inositol 4,5-biphosphate (PIP2) to 1,4,5 inositol triphosphate (IP3) and 1,2-diacylglycerol (DAG) resulting in release of Ca 2+ from intracellular stores and activation of protein kinase C (PKC), respectively. The increased intracellular Ca 2+ concentration activates calmodulin and Ca 2+ / calmodulin-dependent protein kinases (CaM kinases) [28,29] to phosphorylate and activate transcription factors as activating transcription factor 1 (ATF-1), cAMPresponse-element binding protein (CREB), nerve growth factor IB (NGFIB), and nuclear receptor related 1 protein (NURR1) that combined to specific cis-acting series in the 5′ region of CYP11B2 [30]. The acute stimulation mediated by angiotensin II can stimulate rapid aldosterone synthesis either de novo or from intermediate compounds in the steroidogenic pathway.…”

ACTH Action on StAR Biology

“…ACTH binds to its cognate 7-transmembrane G-protein coupled receptor, the melanocortin 2 receptor (encoded by the MC2R gene) that is located at the plasma membrane of adrenal fasciculata cells. ACTH binding to MC2R results in activation of multiple signal transduction pathways with the cAMP-dependent protein kinase A (cAMP-PKA) pathway being central to hormone-dependent activation of adrenal glucocorticoid and androgen synthesis (reviewed in Gallo-Payet and Payet, 2003; Spat et al, 2016). All steroid hormones are produced from cholesterol and the steroidogenic enzymes in cortisol synthesis, the major adrenal steroid produced in response to ACTH, have been reviewed in detail (Miller and Auchus, 2011).…”