Fig. 1: Physiology of adrenal aldosterone production and the mechanism of mutations in PA.

a Under resting conditions, voltage-gated calcium channels are closed due to a high potassium conductance and the resulting hyperpolarized membrane potential. b Physiological stimuli of glomerulosa cells include angiotensin II and hyperkalemia, leading to depolarization, followed by the opening of voltage-gated calcium channels, the signal for aldosterone synthase expression and aldosterone production. c KCNJ5 variants (as somatic mutations in APAs and germline mutations in FH-III) change the ion selectivity of the potassium channel, permitting sodium influx and the depolarization of the cell membrane. d Mutations of CACNA1H (as germline mutations in FH-IV) and CACNA1D (as somatic mutations in APAs and germline mutations in PASNA syndrome) directly cause increased calcium permeability. e The higher chloride permeability of CLCN2 variants (as germline mutations in FH-II) depolarizes glomerulosa cells by chloride efflux. f The ACTH-dependent expression of a hybrid variant of CYP11B2 (as germline mutation in FH-I) in zona fasciculata cells directly increases hybrid gene expression. g Variants of ATP1A1 and ATP2B3 (as somatic mutations in APAs) lead to increased permeability for sodium or protons and thereby depolarize glomerulosa cells. h The underlying mechanism of elevated aldosterone production by variants of CTNNB1 (as somatic mutations in APAs) is incompletely understood. AT1R, angiotensin II receptor type I; MC2R, adrenocorticotropic hormone receptor