Role of KCNJ5 in familial and sporadic primary aldosteronism

Nat Rev Endocrinol. 2013 Feb;9(2):104-12. doi: 10.1038/nrendo.2012.230. Epub 2012 Dec 11.

Abstract

Primary aldosteronism is characterised by the dysregulation of aldosterone production and comprises both sporadic forms, caused by an aldosterone-producing adenoma or bilateral adrenal hyperplasia, and familial forms (familial hyperaldosteronism types I, II and III). The two principal physiological regulators of aldosterone synthesis are angiotensin II and serum K(+), which reverse the high resting K(+) conductance and hyperpolarized membrane potential of adrenal glomerulosa cells. The resulting membrane depolarization causes the opening of voltage-gated Ca(2+) channels and an increase in intracellular Ca(2+) that stimulates aldosterone biosynthesis. Point mutations in the KCNJ5 gene, which encodes the G-protein-activated inward rectifier K(+) channel 4 (GIRK4), have been implicated in the pathogenesis of both sporadic and familial forms of primary aldosteronism. These mutations interfere with the selectivity filter of GIRK4 causing Na(+) entry, cell depolarization and Ca(2+) channel opening, resulting in constitutive aldosterone production. Seven families with familial hyperaldosteronism caused by KCNJ5 germline mutations have so far been described, and multicentre studies have reported KCNJ5 mutations in approximately 40% of sporadic aldosterone-producing adenomas. Herein, we review the role of GIRK4 in adrenal pathophysiology and provide an overview of the clinical and biochemical phenotypes resulting from KCNJ5 mutations in patients with sporadic and familial primary aldosteronism.

Publication types

  • Review

MeSH terms

  • Adrenal Glands / physiology
  • Aldosterone / physiology
  • Animals
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism*
  • Humans
  • Hyperaldosteronism / genetics*
  • Hyperaldosteronism / physiopathology
  • Mutation

Substances

  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • KCNJ5 protein, human
  • Aldosterone