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首页> 外文期刊>Endocrinology >Pharmacology and pathophysiology of mutated KCNJ5 found in adrenal aldosterone-producing adenomas
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Pharmacology and pathophysiology of mutated KCNJ5 found in adrenal aldosterone-producing adenomas

机译：在产生肾上腺醛固酮的腺瘤中发现的突变的KCNJ5的药理和病理生理

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摘要

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 Ca2+ channels. The aim of this study was to further investigate the effects of mutated KCNJ5 channels on intracellular Na + and Ca2+ 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 Ca2+ appeared to be caused by activation of voltage-gated Ca2+ channels and by an impairment of Ca2+ extrusion by Na+/Ca2+ exchangers. The mutated KCNJ5 exhibited a pharmacological profile that differed from the one of wild-type channels. Mutated KCNJ5 was less Ba2+ 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.
机译：在40％的醛固酮生成腺瘤（APA）中发现了钾通道KCNJ5的体细胞突变。 ACN相关的KCNJ5突变导致病理性Na +渗透性和胞浆Ca 2+升高，后者可能是通过使膜去极化并激活电压门控的Ca2 +通道引起的。这项研究的目的是进一步研究突变的KCNJ5通道对人肾上腺皮质NCI-H295R细胞内Na +和Ca2 +稳态的影响。突变体KCNJ5的表达导致细胞内Na +增加2倍，同时导致细胞内Ca 2+大量增加。 Ca2 +的增加似乎是由于电压门控Ca2 +通道的激活以及Na + / Ca2 +交换剂对Ca2 +挤出的损害所致。突变的KCNJ5表现出与野生型通道之一不同的药理特性。突变的KCNJ5对Ba2 +和tertiapin-Q的敏感性较低，但被Na +和Ca 2+转运蛋白（如维拉帕米和阿米洛利）的阻滞剂抑制。这些药物的临床使用可能会影响具有KCNJ5突变的APA患者的醛固酮水平。这可能暗示了APA的诊断测试，并可能提供新的治疗策略。

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