Journal of Endocrinology

Traditional regulators of aldosterone production and their signaling pathways. The traditional aldosterone secretagogues are angiotensin II (AngII), elevated extracellular potassium (K+) levels and adrenocorticotrophic hormone (ACTH), which function through different signal transduction pathways. (A) AngII binds to angiotensin II type 1 receptors (AT1R) to activate phosphoinositide-specific phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to generate inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ binds to IP₃ receptors (IP₃R) on the endoplasmic reticulum (ER) to release ER calcium (Ca²⁺) ions and increase cytosolic Ca²⁺ levels. The increase in intracellular Ca²⁺ concentration activates Ca²⁺/calmodulin-dependent protein kinases (CaMK) that can phosphorylate and activate various members of the cAMP response element-binding protein (CREB)/ activating transcription factor (ATF) family of transcription factors (represented as CREB). This family, as well as Nurr1, the levels of which are also elevated, can induce the expression of genes encoding steroidogenic proteins, such as steroidogenic acute regulatory protein (StAR) and CYP11B2 (coding for aldosterone synthase). AngII also increases Ca²⁺ influx through voltage-dependent Ca²⁺ channels and store-operated Ca²⁺ channels. The other second messenger produced by PLC activity, DAG, activates the protein kinase C (PKC) family of isoenzymes, some of which phosphorylate and activate protein kinase D (PKD); PKD is also known to phosphorylate and activate members of the CREB family of transcription factors. PKC can also activate extracellular signal-regulated kinase-1/2 (ERK), which is able to phosphorylate and activate cholesterol ester hydrolase, to release cholesterol from its storage as cholesteryl ester in lipid droplets, and likely also StAR. DAG can also be generated from the phosphatidic acid (PA) produced by phospholipase D (PLD), which is also activated by AngII and underlies steroidogenesis, although PA can itself serve as a second messenger to mediate the activation of various enzymes (reviewed in Bollag 2016). In addition, AngII working through the AT1R activates Src family kinases (SFK), which can also stimulate PKD activity and appear to underlie aldosterone production. Finally, AngII can also activate JAK2 (not shown). (B) An elevated extracellular K+ level uses many of the same signal transduction pathways as AngII. In this case, an increased K+ concentration depolarizes the glomerulosa cell to open voltage-dependent Ca²⁺ channels, increase intracellular Ca²⁺ levels and activate CaMK, with its downstream targets. There is evidence that K+, like AngII, may also induce phosphoinositide hydrolysis, through an unknown mechanism, although controversy remains concerning this point. Elevated K⁺ also seems to activate PKC and PLD (Betancourt-Calle et al. 2001), which likely play similar roles as in AngII’s effects. Another signal that may or may not be used by elevated K⁺ levels to mediate steroidogenesis is the adenylate cyclase (AC)/cAMP/cAMP-dependent protein kinase (also known as protein kinase A or PKA) pathway. PKA is also known to phosphorylate and activate CREB family transcription factors as well as StAR. (C) ACTH stimulates aldosterone production by binding to its receptor, the melanocortin 2 receptor (MC2R), to activate AC that converts ATP to cAMP. cAMP then stimulates the activity of PKA, thereby activating CREB family transcription factors and StAR. ACTH also increases Ca²⁺ influx through an unclear mechanism, and the resulting increased Ca²⁺ cytosolic levels can activate CaMK, with its downstream effectors. These pathways have been recently reviewed in Bollag (2014).