Coordination of membrane excitability through a GIRK1 signaling complex in the atria
Coordination of membrane excitability through a GIRK1 signaling complex in the atria
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DOI：
10.1074/jbc.m312861200
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发表时间：
2004-05-28
影响因子：
4.8
通讯作者：
Ivanova-Nikolova, TT
中科院分区：
文献类型：
--
作者：
Nikolov, EN;Ivanova-Nikolova, TT
心率的控制是一个复杂的过程，它整合了多种G蛋白偶联受体和离子通道的功能。其中，G蛋白调节的窦房结和心房内向整流钾通道（GIRK或K-ACh）在心率的逐搏调节中起主要作用。心房K-ACh通道是由两个成孔亚基GIRK1和GIRK4组成的异四聚体蛋白。在m（2）-毒蕈碱乙酰胆碱受体（M2R）刺激后，通过G蛋白β γ亚单位（G β γ）与通道的直接结合来赋予K-ACh通道激活。在这里，我们表明，心房K-ACh通道组装在一个信号复合物与G β，G蛋白偶联受体激酶，环腺苷酸依赖性蛋白激酶，两个蛋白磷酸酶，PP1和PP2A，受体活化C激酶1，和肌动蛋白。这种复合物将使K-ACh通道能够快速整合β-肾上腺素能和M2R信号在膜中，它提供了对不同转导途径空间整合的一般原则的见解。此外，在α-肾上腺素能受体刺激后，相同的复合物可能将蛋白激酶C（PKC）募集到K-ACh通道。我们的电生理记录从单个心房K-ACh通道揭示了一个有效的抑制Gbetagamma诱导的通道活性的PKC，从而验证了所观察到的复杂的相互连接的网站，信号分子聚集执行协调控制膜兴奋性的生理意义。
Control of heart rate is a complex process that integrates the function of multiple G protein-coupled receptors and ion channels. Among them, the G protein-regulated inwardly rectifying K+ (GIRK or K-ACh) channels of sinoatrial node and atria play a major role in beat-to-beat regulation of the heart rate. The atrial K-ACh channels are heterotetrameric proteins that consist of two pore-forming subunits, GIRK1 and GIRK4. Following m(2)-muscarinic acetylcholine receptor (M2R) stimulation, K-ACh channel activation is conferred by the direct binding of G protein betagamma subunits (Gbetagamma) to the channel. Here we show that atrial K-ACh channels are assembled in a signaling complex with Gbetagamma, G protein-coupled receptor kinase, cyclic adenosine monophosphate-dependent protein kinase, two protein phosphatases, PP1 and PP2A, receptor for activated C kinase 1, and actin. This complex would enable the K-ACh channels to rapidly integrate beta-adrenergic and M2R signaling in the membrane, and it provides insight into general principles governing spatial integration of different transduction pathways. Furthermore, the same complex might recruit protein kinase C (PKC) to the K-ACh channel following alpha-adrenergic receptor stimulation. Our electrophysiological recordings from single atrial K-ACh channels revealed a potent inhibition of Gbetagamma-induced channel activity by PKC, thus validating the physiological significance of the observed complex as interconnecting site where signaling molecules congregate to execute a coordinated control of membrane excitability.