Fig. 1(A) Normally, AT1 receptor (AT1R) activation induces depolarization as a result of inactivation of the potassium channel Kir3.4 and Na+K+-ATPase. This depolarization triggers influx of Ca2+ through voltage-gated Ca2+ channels (e.g., calcium channel, voltage-dependent, L type, alpha 1D subunit [Cav1.3]), and the resultant rise in intracellular Ca2+ activates the aldosterone synthase gene cytochrome P450 family 11 subfamily B member 2 (CYP11B2). Ca2+-ATPase (e.g., ATPase plasma membrane Ca2+ transporting 3 [ATP2B3]) subsequently shuttles Ca2+ outside the cell. (B) In cells harboring CYP11B1-CYP11B2 gene fusion event, increased CYP11B2 synthesis is controlled by the adrenocorticotropic hormone (ACTH) through its melanocortin receptor 2 (MCR2) receptor. (C) Germline gain of function mutations in chloride voltage-gated channel 2 (CLCN2) chloride channel promotes export of Cl− ions, depolarization of the plasma membrane, and opening of voltage-gated Ca2+ channels. (D) Potassium inwardly rectifying channel subfamily J member 5 (KCNJ5) mutations change the selectivity of the Kir3.4 allowing for Na+ influx. Increased concentration of Na+ ions causes depolarization in the absence of AT1R stimulation. (E) Mutations in calcium voltage-gated channel subunit alpha1 D/H (CACNA1D/1H) subunits increase conductance of Ca2+, (F) whereas mutations in ATP2B3 prevent removal of Ca2+ ions from the cell; both of these mutations increase intracellular Ca2+ concentration and activate CYP11B2 transcription and aldosterone synthesis. Ion channel mutations (encoded by the CLCN2, KCNJ5, CACNA1D/1H, and ATP2B3) in the adrenal glomerulosa cell are linked to excessive aldosterone production. FH2, familial hyperaldosteronism type 2; PASNA, Primary Aldosteronism with Seizures and Neurologic Abnormalities.
Fig. 2Wnt-induced activation of Frizzled (Fzd) leads to inhibition of glycogen synthase kinase 3 (GSK3) in a ß-catenin independent way. GSK3 inhibition inactivates its substrate TSC, TSC2 (tuberous sclerosis complex 2 or tuberin). TSC2 is a tumor suppressor complex that controls mammalian target of rapamycin (mTOR) activity through the regulatory Rheb protein. In addition to Fzd, LDL receptor related protein 5/6 (LRP5/6) co-receptor and GSK3, the scaffold proteins of the canonical Wnt cascade, Dvl, and Axin, have been implicated in signal transduction. mTOR activation can in turn cause upregulation of the inflammatory pathways through nuclear factor κb (NF-κb) and increased aldosterone synthesis through yet unknown mechanism. GDP, guanosine-5′-triphosphate; mTORC1, mammalian target of rapamycin complex 1; GTP, guanosine-5′-diphosphate; IL, interleukin; TNF, tumor necrosis factor.