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Published on: September 15, 2017
Pharmacology and pathophysiology of mutated KCNJ5 found in adrenal aldosterone-producing adenomas
1Medical 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.
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.
Insights
Mutations in the KCNJ5 gene, common in aldosterone-producing adenomas, disrupt ion balance, increasing sodium and calcium levels. This suggests potential new treatments targeting ion channels for these tumors.
Area of Science:
- Endocrinology
- Molecular Biology
- Ion Channel Physiology
Background:
- Somatic mutations in the potassium channel KCNJ5 gene are identified in 40% of aldosterone-producing adenomas (APAs).
- These KCNJ5 mutations are linked to abnormal sodium permeability and elevated intracellular calcium, potentially through membrane depolarization and voltage-gated calcium channel activation.
Purpose of the Study:
- To investigate the impact of mutated KCNJ5 channels on intracellular sodium (Na+) and calcium (Ca2+) homeostasis.
- To explore the pharmacological differences between wild-type and mutated KCNJ5 channels.
Main Methods:
- Utilized human adrenocortical NCI-H295R cells expressing mutated KCNJ5.
- Measured intracellular Na+ and Ca2+ levels.
- Assessed the effects of pharmacological agents, including verapamil and amiloride, on ion transport.
Main Results:
- Expression of mutated KCNJ5 resulted in a twofold increase in intracellular Na+ and a significant rise in intracellular Ca2+.
- The elevated Ca2+ was attributed to voltage-gated Ca2+ channel activation and impaired Na+/Ca2+ exchanger function.
- Mutated KCNJ5 showed altered sensitivity to blockers, being less sensitive to Ba2+ and tertiapin-Q but inhibited by verapamil and amiloride.
Conclusions:
- Mutated KCNJ5 channels significantly disrupt ion homeostasis in adrenocortical cells.
- The distinct pharmacological profile of mutated KCNJ5 suggests potential therapeutic targets.
- Drugs like verapamil and amiloride may influence aldosterone levels in APA patients with KCNJ5 mutations, indicating new diagnostic and therapeutic possibilities.
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