Figure 2. Proposed molecular mechanism responsible for autonomous aldosterone production in adrenal cells carrying mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D.

A. GIRK4 physiologically keeps the cell in a hyperpolarized state. The mutation, located near or within the selectivity filter of the channel, cause a loss of ion selectivity, Na⁺ entry, cell membrane depolarization and activation of membrane calcium channels. B. Na+/K⁺ ATPase sustains a transmembrane concentration gradient for potassium and sodium. Mutations in the ATP1A1 gene affecting the ion binding capacity disrupt this function leading to cell membrane depolarization. C. Ca²⁺ ATPase3 physiologically pumps calcium out of the cell. Loss of this function leads to an increase in intracellular calcium. D. Cav1.3 is the α1 (pore-forming) subunit of an L-type (long-lasting) voltage-gated calcium channel. Mutations in CACNA1D causes activation of the channel at a less depolarized state, suppresses the channel’s inactivation or directly increases the currents flux of calcium.