Sui J L, Chan K W, Logothetis D E
Department of Physiology and Biophysics, Mount Sinai School of Medicine, City University of New York, New York 10029, USA.
J Gen Physiol. 1996 Nov;108(5):381-91. doi: 10.1085/jgp.108.5.381.
Muscarinic potassium channels (KACh) are composed of two subunits, GIRK1 and GIRK4 (or CIR), and are directly gated by G proteins. We have identified a novel gating mechanism of KACh, independent of G-protein activation. This mechanism involved functional modification of KACh which required hydrolysis of physiological levels of intracellular ATP and was manifested by an increase in the channel mean open time. The ATP-modified channels could in turn be gated by intracellular Na+, starting at approximately 3 mM with an EC50 of approximately 40 mM. The Na(+)-gating of KACh was operative both in native atrial cells and in a heterologous system expressing recombinant channel subunits. Block of the Na+/K+ pump (e.g., by cardiac glycosides) caused significant activation of KACh in atrial cells, with a time course similar to that of Na+ accumulation and in a manner indistinguishable from that of Na(+)-mediated activation of the channel, suggesting that cardiac glycosides activated KACh by increasing intracellular Na+ levels. These results demonstrate for the first time a direct effect of cardiac glycosides on atrial myocytes involving ion channels which are critical in the regulation of cardiac rhythm.
毒蕈碱钾通道（KACh）由两个亚基GIRK1和GIRK4（或CIR）组成，并由G蛋白直接门控。我们发现了一种KACh的新型门控机制，独立于G蛋白激活。该机制涉及KACh的功能修饰，这需要水解生理水平的细胞内ATP，并表现为通道平均开放时间增加。ATP修饰的通道反过来可以被细胞内Na +门控，从大约3 mM开始，EC50约为40 mM。KACh的Na +门控在天然心房细胞和表达重组通道亚基的异源系统中均有效。Na + / K +泵的阻断（例如，通过强心苷）导致心房细胞中KACh的显著激活，其时间进程与Na +积累相似，并且与Na +介导的通道激活方式无法区分，表明强心苷通过增加细胞内Na +水平来激活KACh。这些结果首次证明了强心苷对心房肌细胞的直接作用涉及对心律调节至关重要的离子通道。
