Pharmacology and pathophysiology of mutated KCNJ5 found in adrenal aldosterone-producing adenomas.

Somatic mutations of the potassium channel KCNJ5 are found in 40% of aldosterone producing adenomas (APAs). APA-related mutations of KCNJ5 lead to a pathological Na(+) permeability and a rise in cytosolic Ca(2+), the latter presumably by depolarizing the membrane and activating voltage-gated Ca(2+) channels. The aim of this study was to further investigate the effects of mutated KCNJ5 channels on intracellular Na(+) and Ca(2+) homeostasis in human adrenocortical NCI-H295R cells. Expression of mutant KCNJ5 led to a 2-fold increase in intracellular Na(+) and, in parallel, to a substantial rise in intracellular Ca(2+). The increase in Ca(2+) appeared to be caused by activation of voltage-gated Ca(2+) channels and by an impairment of Ca(2+) extrusion by Na(+)/Ca(2+) exchangers. The mutated KCNJ5 exhibited a pharmacological profile that differed from the one of wild-type channels. Mutated KCNJ5 was less Ba(2+) and tertiapin-Q sensitive but was inhibited by blockers of Na(+) and Ca(2+)-transporting proteins, such as verapamil and amiloride. The clinical use of these drugs might influence aldosterone levels in APA patients with KCNJ5 mutations. This might implicate diagnostic testing of APAs and could offer new therapeutic strategies.

TASK1 and TASK3 potassium channels: determinants of aldosterone secretion and adrenocortical zonation.

Potassium channels control the membrane voltage of aldosterone-producing zona glomerulosa cells. They are responsible for the unique K(+) sensitivity of these cells and are important molecular targets of angiotensin II signaling. Among the 78 pore-forming K(+) channels in human genome only a few are found in adrenal glands. The 2-P-domain K(+) channels TASK1 and TASK3 are strongly expressed in the adrenal cortex and produce a background K(+) conductance, which is pivotal for the regulation of the aldosterone secretion in zona glomerulosa cells. Disruption of the TASK1 gene in mice resulted in an autonomous aldosterone production and caused a remarkable aberrant expression of aldosterone synthase in zona fasciculata cells that normally produce glucocorticoids. After puberty, only in male mice aldosterone production was switched off in the zona fasciculata and regular zonation of aldosterone synthase occurred. In double mutant TASK1(-/-)/TASK3(-/-) mice, also adult male mice displayed primary hyperaldosteronism. Therefore, these knockout mice are interesting models to study mechanisms of autonomous aldosterone production and adrenocortical zonation. These data suggest that modifications of the adrenocortical K(+) conductances could also contribute to autonomic aldosterone production and primary hyperaldosteronism in humans.