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Block of cardiac ATP-sensitive K+ channels by external divalent cations is modulated by intracellular ATP. Evidence for allosteric regulation of the channel protein

机译:外部二价阳离子对心脏ATP敏感的K +通道的阻滞是由细胞内ATP调节的。通道蛋白的变构调节的证据

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摘要

We have investigated the interactions between extracellular divalent cations and the ATP-sensitive potassium channel in single guinea pig ventricular cells and found that, under whole-cell patch clamp recording conditions, extracellularly applied Co2+, Cd2+, and Zn2+ block current through the ATP-sensitive K channel (IKATP). The respective Kd's for block of IKATP by Cd2+ and Zn2+ are 28 and 0.46 microM. The Kd for Co2+ is > 200 microM. Extracellular Ca2+ and Mg2+ appear to have no effect at concentrations up to 1 and 2 mM, respectively. Block of IKATP by extracellular cations is not voltage dependent, and both onset and recovery from block occur within seconds. Single-channel experiments using the inside-out patch configuration show that internally applied Cd2+ and Zn2+ are not effective blockers of IKATP. Experiments in the outside-out patch configuration confirm that the divalent cations interact directly with IKATP channel activity. Our study also shows that this block of IKATP is dependent on intracellular ATP concentrations. Under whole-cell conditions, when cells are dialyzed with [ATP]pipette = 0, the degree of cation block is reduced. This dependence on intracellular ATP was confirmed at the single-channel level by experiments in excised, inside-out patch configurations. Our results show that some, but not all, divalent cations inhibit current through IKATP channels by binding to sites that are not within the transmembrane electric field, but are on the extracellular membrane surface. The interdependence of internal ATP and external divalent cation binding is consistent with an allosteric interaction between two binding sites and is highly suggestive of a modulatory mechanism involving conformational change of the channel protein.
机译:我们研究了单个豚鼠心室细胞中细胞外二价阳离子与ATP敏感性钾通道之间的相互作用,发现在全细胞膜片钳记录条件下,细胞外施加的Co2 +,Cd2 +和Zn2 +阻断了通过ATP敏感性的电流K频道(IKATP)。 Cd2 +和Zn2 +阻断IKATP的Kd分别为28和0.46 microM。 Co2 +的Kd> 200 microM。细胞外Ca2 +和Mg2 +在浓度分别高达1和2 mM时似乎没有作用。细胞外阳离子对IKATP的阻滞与电压无关,并且起效和从阻滞中恢复均在数秒内发生。使用由内而外的贴片配置进行的单通道实验表明,内部施加的Cd2 +和Zn2 +不是IKATP的有效阻断剂。从外而外的贴剂配置中的实验证实,二价阳离子与IKATP通道活性直接相互作用。我们的研究还表明,IKATP的这种阻滞取决于细胞内ATP的浓度。在全细胞条件下,当用[ATP]移液器= 0透析细胞时,阳离子阻滞的程度会降低。对细胞内ATP的这种依赖性在单通道水平上通过切除,由内而外的贴剂配置进行了实验证实。我们的结果表明,某些(但不是全部)二价阳离子通过结合到不在跨膜电场内而是在细胞外膜表面的位点来抑制通过IKATP通道的电流。内部ATP和外部二价阳离子结合的相互依赖性与两个结合位点之间的变构相互作用相一致,并且高度暗示了涉及通道蛋白构象变化的调节机制。

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  • 年度 1993
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