Selectivity of Digitalis Glycosides for Isoforms of Human Na,K-ATPase
Selectivity of Digitalis Glycosides for Isoforms of Human Na,K-ATPase
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DOI：
10.1074/jbc.m110.119248
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发表时间：
2010-06-18
影响因子：
4.8
通讯作者：
Karlish, Steven J. D.
中科院分区：
文献类型：
--
作者：
Katz, Adriana;Lifshitz, Yael;Karlish, Steven J. D.
Na， k - atp酶有4个α亚基（α 1-4）和3个β亚基（β 1-3）同工型，具有不同的组织特异性分布和生理功能。α 2被认为在心脏和平滑肌收缩中起关键作用，是心脏糖苷的重要靶点。α 2选择性心脏糖苷可以为α 2的生理和药理学特性提供重要的见解。利用毕赤酵母中表达的人Na、k - atp酶的α 1 β 1、α 2 β 1和α 3 β 1异构体和纯化的洗涤剂可溶性异构体蛋白，对大量心脏糖苷的异构体选择性进行了评估。洋地黄苷、地高辛、β -甲基地高辛和地地黄苷的结合亲和力显示出对α 2/ β 3对α 1 （K-D α 1 > α 2 = α 3）的适度但高度显著的选择性（高达4倍）。相比之下，沃巴因对α 1比α 2 （K-D α 1）表现出中等选择性（约2.5倍）
There are four isoforms of the alpha subunit (alpha 1-4) and three isoforms of the beta subunit (beta 1-3) of Na,K-ATPase, with distinct tissue-specific distribution and physiological functions. alpha 2 is thought to play a key role in cardiac and smooth muscle contraction and be an important target of cardiac glycosides. An alpha 2-selective cardiac glycoside could provide important insights into physiological and pharmacological properties of alpha 2. The isoform selectivity of a large number of cardiac glycosides has been assessed utilizing alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1 isoforms of human Na, K-ATPase expressed in Pichia pastoris and the purified detergent-soluble isoform proteins. Binding affinities of the digitalis glycosides, digoxin, beta-methyl digoxin, and digitoxin show moderate but highly significant selectivity (up to 4-fold) for alpha 2/beta 3 over alpha 1 (K-D alpha 1 > alpha 2 = alpha 3). By contrast, ouabain shows moderate selectivity (approximate to 2.5-fold) for alpha 1 over alpha 2 (K-D alpha 1