title: Role of KCNJ5 in familial and sporadic primary aldosteronism.
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.
authors.affiliation: University of Torino, Department of Medical Sciences, Division of Internal Medicine and Hypertension, Italy. paolo.mulatero@ unito.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Mulatero
authors.forename: Silvia
authors.initials: S
authors.lastname: Monticone
authors.forename: William E
authors.initials: WE
authors.lastname: Rainey
authors.forename: Franco
authors.initials: F
authors.lastname: Veglio
authors.forename: Tracy Ann
authors.initials: TA
authors.lastname: Williams
mesh_terms: D000311:Adrenal Glands / Q000502:physiology; D000450:Aldosterone / Q000502:physiology; D000818:Animals; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D000450:Aldosterone