title: 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.
authors: Medical Cell Biology (P.T., J.S., E.H., I.T., C.S., S.B., R.W.), University of Regensburg, 93053 Regensburg, Germany; Laboratoire de PhysioMédecine Moléculaire (D.P., J.B.), Centre National de la Recherche Scientifique, and Université de Nice Sophia Antipolis, FRE3472-Laboratoire de PhysioMédecine Moléculaire, 06108 Nice Cedex, France; Laboratories of Excellence, Ion Channel Science and Therapeutics (D.P., J.B.), France; and Medizinische Klinik und Poliklinik IV (F.B., M.R.), Ludwig-Maximilians-Universität, 80336 Munich, Germany.
authors: P
authors: P
authors: Tauber
authors: D
authors: D
authors: Penton
authors: J
authors: J
authors: Stindl
authors: E
authors: E
authors: Humberg
authors: I
authors: I
authors: Tegtmeier
authors: C
authors: C
authors: Sterner
authors: F
authors: F
authors: Beuschlein
authors: M
authors: M
authors: Reincke
authors: J
authors: J
authors: Barhanin
authors: S
authors: S
authors: Bandulik
authors: R
authors: R
authors: Warth
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism*; D000584:Amiloride / Q000737:chemistry; D001464:Barium / Q000737:chemistry; D001514:Bee Venoms / Q000737:chemistry; D002118:Calcium / Q000737:chemistry; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D018408:Patch-Clamp Techniques; D010539:Permeability; D011188:Potassium / Q000737:chemistry; D020033:Protein Isoforms / Q000235:genetics; D012313:RNA / Q000378:metabolism; D012964:Sodium / Q000737:chemistry; D014700:Verapamil / Q000737:chemistry
chemical_list: D001514:Bee Venoms; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D020033:Protein Isoforms; D001464:Barium; C029738:tertiapin; D000450:Aldosterone; D012313:RNA; D000584:Amiloride; D012964:Sodium; D014700:Verapamil; D011188:Potassium; D002118:Calcium