Isoform-specific刺激心脏钠-钾泵的配糖体的摩尔浓度。

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高J, Wymore RS,王Y, Gaudette GR, Krukenkamp IB,科恩Mathias RT

Isoform-specific刺激心脏钠-钾泵的配糖体的摩尔浓度。

J创杂志。2002年4月,119 (4):297 - 312。

PubMed ID
11929882 (在PubMed
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文摘

众所周知,微摩尔的毫克分子浓度的心脏苷抑制钠-钾泵的活动,然而,一些早期的报告显示这些苷刺激活动的摩尔浓度。这些早期的报告是基于间接测量在多细胞的准备工作,因此,有一些不确定性是否离子积累/损耗而不是泵刺激引起的观测。这里,我们利用全细胞膜片钳技术在孤立的心脏细胞直接测量钠/钾泵电流(I (P))条件,减少离子积累的可能性/损耗导致观察到的效果。在豚鼠心室细胞,摩尔浓度dihydro-ouabain (DHO)造成了输出电流,似乎是由于刺激我(P),因为以下几点:(1)缺席在0毫米(K (+)) (o),就像我(P);(2)在0毫米缺席(Na (+)) (i),就像我(P);(3)在减少(Na (+)) (i),向外电流减少的比例减少(P);(4)钒酸被细胞内,就像我(P)。我们以前的工作建议豚鼠心室细胞coexpressα(1)-和α(2)钠-钾泵的亚型。我的刺激(P)似乎是通过刺激α糖苷亲和力高(2)同种型而非α(1)同种型,因为以下几点:(1)调节信号,特别是增加活动的α(2)同种型刺激的振幅增加;(2)调节信号,特别是改变α(1)同种型的活动并不影响刺激; (3) changes in [K(+)](o) that affected activity of the alpha(1)-isoform, but not the alpha(2)-isoform, did not affect the stimulation; (4) myocytes from one group of guinea pigs expressed the alpha(1)-isoform but not the alpha(2)-isoform, and these myocytes did not show the stimulation. At 10 nM DHO, total I(P) increased by 35 +/- 10% (mean +/- SD, n = 18). If one accepts the hypothesis that this increase is due to stimulation of just the alpha(2)-isoform, then activity of the alpha(2)-isoform increased by 107 +/- 30%. In the guinea pig myocytes, nanomolar ouabain as well as DHO stimulated the alpha(2)-isoform, but both the stimulatory and inhibitory concentrations of ouabain were approximately 10-fold lower than those for DHO. Stimulation of I(P) by nanomolar DHO was observed in canine atrial and ventricular myocytes, which express the alpha(1)- and alpha(3)-isoforms of the Na/K pumps, suggesting the other high glycoside affinity isoform (the alpha(3)-isoform) also was stimulated by nanomolar concentrations of DHO. Human atrial and ventricular myocytes express all three isoforms, but isoform affinity for glycosides is too similar to separate their activity. Nevertheless, nanomolar DHO caused a stimulation of I(P) that was very similar to that seen in other species. Thus, in all species studied, nanomolar DHO caused stimulation of I(P), and where the contributions of the high glycoside affinity alpha(2)- and alpha(3)-isoforms could be separated from that of the alpha(1)-isoform, it was only the high glycoside affinity isoform that was stimulated. These observations support early reports that nanomolar concentrations of glycosides stimulate Na/K pump activity, and suggest a novel mechanism of isoform-specific regulation of I(P) in heart by nanomolar concentrations of endogenous ouabain-like molecules.

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