Pharmacology and Pathophysiology of Mutated KCNJ5 Found in Adrenal Aldosterone-Producing Adenomas

Abstract

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.

An update on novel mechanisms of primary aldosteronism

“…The Gly151Arg and Thr158Ala mutants were also blocked by verapamil but less potently (Tauber et al 2014). Verapamil may not only act on aldosterone secretion by directly blocking the mutated channel but also by inhibiting depolarization-activated voltage-gated Ca 2C channels.…”

“…Increased intracellular calcium concentrations are supposed to be due to opening of voltage-activated Ca 2C channels. Interestingly, in the adrenocortical NCI-H295R cell line, high intracellular Na C impaired Ca 2C export via Na C /Ca 2C exchangers (NCX) and possibly allowed Ca 2C influx through NCX working in reverse transport mode (Tauber et al 2014). Unlike WT GIRK4, which is inhibited by Tertiapin-Q (Jin et al 1999), the mutant GIRK4 channels are only weakly inhibited by Tertiapin-Q (Tauber et al 2014).…”

“…Interestingly, in the adrenocortical NCI-H295R cell line, high intracellular Na C impaired Ca 2C export via Na C /Ca 2C exchangers (NCX) and possibly allowed Ca 2C influx through NCX working in reverse transport mode (Tauber et al 2014). Unlike WT GIRK4, which is inhibited by Tertiapin-Q (Jin et al 1999), the mutant GIRK4 channels are only weakly inhibited by Tertiapin-Q (Tauber et al 2014). Rather, in vitro studies have shown that the GIRK4 p.Leu168Arg mutant channel is inhibited by amiloride and, more potently, by the L-type Ca 2C channel blocker verapamil.…”

Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

“…However, loss of K + selectivity in KCNJ5 G151R and KCNJ5 L168R channels as well as loss of sensitivity to the K + channel blockers barium (7) and tertiapin-Q (22) suggest that the pore of mutant channels is sufficiently altered to enable small molecules to block ion passage through the mutant, but not the WT, channel.…”

Progrès récents dans la génétique de l’hyperaldostéronisme primaire

“…Des mutations constitutionnelles de novo du gène CACNA1D ont été décrites chez des sujets ayant une HTA précoce, un hyperaldostéronisme primaire et un tableau neurologique complexe [10]. [35]. Le vérapamil n'agirait donc pas uniquement sur la production d'aldostérone en inhibant les canaux Ca 2+ dépendants du voltage activés par la dépolarisation, mutation germinale a été identifiée dans l'exon 8B du gène CACNA1D sous la forme de la substitution d'une glycine par une asparagine en position 403 (p.Gly403Asp).…”