2. Academic Validation
  3. Mutated KCNJ5 activates the acute and chronic regulatory steps in aldosterone production

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

  • J Mol Endocrinol. 2016 Jul;57(1):1-11. doi: 10.1530/JME-15-0324.
Namita G Hattangady 1,  Shigehiro Karashima 2,  Lucy Yuan 1,  Daniela Ponce-Balbuena 3,  José Jalife 3,  Celso E Gomez-Sanchez 4,  Richard J Auchus 2,  William E Rainey 5,  Tobias Else 6
Affiliations

Affiliations

  • 1 Department of Internal MedicineDivision of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA.
  • 2 Department of Internal MedicineDivision of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA Department of PharmacologyUniversity of Michigan, Ann Arbor, Michigan, USA.
  • 3 Center for Arrhythmia ResearchUniversity of Michigan, Ann Arbor, Michigan, USA.
  • 4 G. V. (Sonny) Montgomery VA Medical Center and Department of MedicineUniversity of Mississippi Medical Center, Jackson, Mississippi, USA.
  • 5 Department of Internal MedicineDivision of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA Department of Molecular and Integrative PhysiologyUniversity of Michigan, Ann Arbor, Michigan, USA.
  • 6 Department of Internal MedicineDivision of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA telse@umich.edu.
PMID: 27099398 DOI: 10.1530/JME-15-0324
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 (KCNJ5(T158A)) on acute and chronic regulation of aldosterone production using an adrenal cell line with a doxycycline-inducible KCNJ5(T158A) gene (HAC15-TRE-KCNJ5(T158A)). Doxycycline incubation caused a time-dependent increase in KCNJ5(T158A) and CYP11B2 mRNA and protein levels. Electrophysiological analyses confirm the loss of inward rectification and increased Na(+) permeability in KCNJ5(T158A)-expressing cells. KCNJ5(T158A) expression also led to the activation of CYP11B2 transcriptional regulators, NURR1 and ATF2. Acutely, KCNJ5(T158A) stimulated the expression of total and phosphorylated steroidogenic acute regulatory protein (StAR). KCNJ5(T158A) 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 KCNJ5(T158A) were inhibited by the L-type CA(2+) channel blocker, verapamil. Overall, KCNJ5(T158A)increases CYP11B2 expression and production of aldosterone, corticosterone and hybrid Steroids by upregulating both acute and chronic regulatory events in aldosterone production, and verapamil blocks KCNJ5(T158A)-mediated pathways leading to aldosterone production.

Keywords

KCNJ5 mutations; adrenal; aldosterone; primary aldosteronism (PA).

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