Recently, the molecular basis of primary aldosteronism has begun to be unraveled, with the discovery of mutations in potassium channel (KCNJ5), ATPases (ATP1A1, ATP2B3), and calcium channel (CACNA1D), and aberrant Wnt/β-catenin signaling.
Such blockers could target CACNA1H or both CACNA1H and the L-type calcium channel CACNA1D that is also expressed in the adrenal gland and mutated in patients with primary aldosteronism.
The high prevalence of mutations in the CACNA1D L-type calcium channel provides a potential actionable therapeutic target that could complement mineralocorticoid blockade and inhibit aldosterone overproduction in some IHA patients.
Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder.