Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis
Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis
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DOI：
10.1038/sj.emboj.7601934
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发表时间：
2008-01-09
期刊：
影响因子：
11.4
通讯作者：
Barhanin, Jacques
中科院分区：
文献类型：
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作者：
Heitzmann, Dirk;Derand, Renaud;Barhanin, Jacques
TASK1 (KCNK3) 和 TASK3 (KCNK9) 是在肾上腺中高表达的双孔域钾通道。 TASK1/TASK3 异二聚体被认为有助于背景电导，其被血管紧张素 II 抑制可刺激醛固酮分泌。我们使用task1(-/-)小鼠来分析该通道在肾上腺功能中的作用。任务1（-/-）表现出严重的醛固酮增多症，与盐摄入、低钾血症和动脉“低肾素”高血压无关。糖皮质激素可以完全治愈醛固酮增多症。醛固酮表型是由肾上腺皮质分区缺陷引起的。醛固酮合酶在通常对应于球状带的外皮层中不存在，但在网状束状带中丰富。年轻小鼠中盐皮质激素稳态和分区受损与性别无关，但仅限于成年雌性小鼠。肾上腺细胞膜片钳实验表明，task3 和其他 K+ 通道补偿了 task1 的缺失。肾上腺分区似乎是一个动态过程，甚至可以在成年期发生。 task1(-/-) 小鼠肾上腺皮质结构的显着变化首次证明了钾通道在发育/分化中的致病作用。
TASK1 (KCNK3) and TASK3 (KCNK9) are two-pore domain potassium channels highly expressed in adrenal glands. TASK1/TASK3 heterodimers are believed to contribute to the background conductance whose inhibition by angiotensin II stimulates aldosterone secretion. We used task1(-/-) mice to analyze the role of this channel in adrenal gland function. Task1(-/-) exhibited severe hyperaldosteronism independent of salt intake, hypokalemia, and arterial 'low-renin' hypertension. The hyperaldosteronism was fully remediable by glucocorticoids. The aldosterone phenotype was caused by an adrenocortical zonation defect. Aldosterone synthase was absent in the outer cortex normally corresponding to the zona glomerulosa, but abundant in the reticulo-fasciculata zone. The impaired mineralocorticoid homeostasis and zonation were independent of the sex in young mice, but were restricted to females in adults. Patch-clamp experiments on adrenal cells suggest that task3 and other K+ channels compensate for the task1 absence. Adrenal zonation appears as a dynamic process that even can take place in adulthood. The striking changes in the adrenocortical architecture in task1(-/-) mice are the first demonstration of the causative role of a potassium channel in development/ differentiation.