On the effect of hyperaldosteronism-inducing mutations in Na/K pumps.
On the effect of hyperaldosteronism-inducing mutations in Na/K pumps.
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DOI：
10.1085/jgp.201711827
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发表时间：
2017-11-06
期刊：
影响因子：
--
通讯作者：
Artigas P
中科院分区：
文献类型：
--
作者：
Meyer DJ;Gatto C;Artigas P
肾上腺腺瘤中突变的Na/K泵被认为是通过涉及去极化内向电流的功能增益效应而引起的醛固酮增多症。Meyer等人的发现。相反，建议Na/K泵突变导致醛固酮增多症的共同机制是功能丧失。原发性醛固酮增多症是一种产生过多的醛固酮并导致高血压的疾病，通常由肾上腺皮质球状带内产生醛固酮的腺瘤引起。在这些腺瘤中发现了编码Na/K泵α1亚单位的ATP1A1的体细胞突变。有人提出，由几个突变泵运输的被动内向电流是一种“功能增益”活动，它会产生膜去极化，并伴随着醛固酮产量的增加。在这里，我们调查通过突变的Na/K泵的内向电流是否足够大，以诱导携带它们的细胞的去极化。我们首先研究了非洲爪哇卵母细胞中表达的这些突变所引起的内向电流，发现这些内向电流在幅度上与野生型外向Na/K泵电流相似。随后，我们对在非洲爪哇卵母细胞中表达的人钠钾泵突变体L104R、delF100-L104、V332G和EETA963S进行了详细的功能评估。结合双电极电压钳和[~3H]哇巴因结合，我们测量了这些内向电流的周转率，并与野生型泵的外向电流周转率进行了比较。我们发现，通过其中两个突变体(EETA963S和L104R)的内向电流的周转率太小，不能引起明显的细胞去极化。另一种高醛固酮诱导突变G99R的电生理特征表明，在许多不同的条件下，包括在调节剂FXYD1存在的情况下，以及在哺乳动物的离子浓度和体温的情况下，都没有内向电流。相反，我们观察到强劲的外向电流，但细胞内Na+和细胞外K+的亲和力显著降低。总之，我们的结果表明，功能丧失是这些Na/K泵突变引起的醛固酮增多症的共同机制。
Mutated Na/K pumps in adrenal adenomas are thought to cause hyperaldosteronism via a gain-of-function effect involving a depolarizing inward current. The findings of Meyer et al. suggest instead that the common mechanism by which Na/K pump mutants lead to hyperaldosteronism is a loss-of-function. Primary aldosteronism, a condition in which too much aldosterone is produced and that leads to hypertension, is often initiated by an aldosterone-producing adenoma within the zona glomerulosa of the adrenal cortex. Somatic mutations of ATP1A1, encoding the Na/K pump α1 subunit, have been found in these adenomas. It has been proposed that a passive inward current transported by several of these mutant pumps is a "gain-of-function" activity that produces membrane depolarization and concomitant increases in aldosterone production. Here, we investigate whether the inward current through mutant Na/K pumps is large enough to induce depolarization of the cells that harbor them. We first investigate inward currents induced by these mutations in Xenopus Na/K pumps expressed in Xenopus oocytes and find that these inward currents are similar in amplitude to wild-type outward Na/K pump currents. Subsequently, we perform a detailed functional evaluation of the human Na/K pump mutants L104R, delF100-L104, V332G, and EETA963S expressed in Xenopus oocytes. By combining two-electrode voltage clamp with [3H]ouabain binding, we measure the turnover rate of these inward currents and compare it to the turnover rate for outward current through wild-type pumps. We find that the turnover rate of the inward current through two of these mutants (EETA963S and L104R) is too small to induce significant cell depolarization. Electrophysiological characterization of another hyperaldosteronism-inducing mutation, G99R, reveals the absence of inward currents under many different conditions, including in the presence of the regulator FXYD1 as well as with mammalian ionic concentrations and body temperatures. Instead, we observe robust outward currents, but with significantly reduced affinities for intracellular Na+ and extracellular K+. Collectively, our results point to loss-of-function as the common mechanism for the hyperaldosteronism induced by these Na/K pump mutants.
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影响因子：
30.8
作者：
Azizan, Elena A. B.;Poulsen, Hanne;Brown, Morris J.
通讯作者：
Brown, Morris J.
DOI：
10.1126/science.1198785
发表时间：
2011-02-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Choi M;Scholl UI;Yue P;Björklund P;Zhao B;Nelson-Williams C;Ji W;Cho Y;Patel A;Men CJ;Lolis E;Wisgerhof MV;Geller DS;Mane S;Hellman P;Westin G;Åkerström G;Wang W;Carling T;Lifton RP
通讯作者：
Lifton RP
影响因子：
4.1
作者：
Gomez-Sanchez, Celso E.;Kuppusamy, Maniselvan;Gomez-Sanchez, Elise P.
通讯作者：
Gomez-Sanchez, Elise P.
影响因子：
3.8
作者：
Artigas, P;Gadsby, DC
通讯作者：
Gadsby, DC
影响因子：
4.8
作者：
Crambert, G;Hasler, U;Geering, K
通讯作者：
Geering, K