Mutated KCNJ5 activates the acute and chronic regulatory steps in aldosterone production

Author:

Hattangady Namita G,Karashima Shigehiro,Yuan Lucy,Ponce-Balbuena Daniela,Jalife José,Gomez-Sanchez Celso E,Auchus Richard J,Rainey William E,Else Tobias

Abstract

Somatic and germline mutations in the inward-rectifying K+ channel (KCNJ5) are a common cause of primary aldosteronism (PA) in aldosterone-producing adenoma and familial hyperaldosteronism type III, respectively. Dysregulation of adrenal cell calcium signaling represents one mechanism for mutated KCNJ5 stimulation of aldosterone synthase (CYP11B2) expression and aldosterone production. However, the mechanisms stimulating acute and chronic production of aldosterone by mutant KCNJ5 have not been fully characterized. Herein, we defined the effects of the T158A KCNJ5 mutation (KCNJ5T158A) on acute and chronic regulation of aldosterone production using an adrenal cell line with a doxycycline-inducible KCNJ5T158A gene (HAC15-TRE-KCNJ5T158A). Doxycycline incubation caused a time-dependent increase in KCNJ5T158A and CYP11B2 mRNA and protein levels. Electrophysiological analyses confirm the loss of inward rectification and increased Na+ permeability in KCNJ5T158A-expressing cells. KCNJ5T158A expression also led to the activation of CYP11B2 transcriptional regulators, NURR1 and ATF2. Acutely, KCNJ5T158A stimulated the expression of total and phosphorylated steroidogenic acute regulatory protein (StAR). KCNJ5T158A expression increased the synthesis of aldosterone and the hybrid steroids 18-hydroxycortisol and 18-oxocortisol, measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS). All of these stimulatory effects of KCNJ5T158A were inhibited by the L-type Ca2+ channel blocker, verapamil. Overall, KCNJ5T158Aincreases CYP11B2 expression and production of aldosterone, corticosterone and hybrid steroids by upregulating both acute and chronic regulatory events in aldosterone production, and verapamil blocks KCNJ5T158A-mediated pathways leading to aldosterone production.

Publisher

Bioscientifica

Subject

Endocrinology,Molecular Biology

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