HERG K+ channel activity is regulated by changes in phosphatidyl inositol 4,5-bisphosphate
HERG K+ channel activity is regulated by changes in phosphatidyl inositol 4,5-bisphosphate
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DOI：
10.1161/hh2401.101375
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发表时间：
2001-12-07
影响因子：
20.1
通讯作者：
McDonald, TV
中科院分区：
文献类型：
--
作者：
Bian, JS;Cui, J;McDonald, TV
自主神经刺激控制心率和心肌兴奋性，可能是获得性和遗传性心律失常的基础。磷脂酰肌醇二磷酸（PIP 2）浓度的变化由几种毒蕈碱和肾上腺素能受体的激活引起。我们试图研究PIP-2的变化是否可以改变HERG K+通道活性的方式类似于内向整流通道。内透析的PIP 2（10 μ mol/L）使K+电流幅值增加，并使激活的电压依赖性向超极化方向移动。升高的PIP 2加速活化并减慢失活动力学。当10 μ mol/L PIP 2作用于离体贴片时。单通道电导没有发生显著变化，表明PIP 2依赖性效应主要是由于改变的通道门控。PIP 2显著减弱了我们通常在贴片切除后观察到的HERG通道活性的下降，这表明通道下降部分是由于PIP 2的膜耗尽。在全细胞移液器溶液中包含中和抗PIP 2单克隆抗体产生了与PIP 2相反的效果。PIP 2-HERG相互作用的生理相关性得到了我们的发现的支持，即苯丙氨酸降低了共表达α 1A受体和HERG的细胞中的K+电流密度。然而，α-肾上腺素能刺激的作用被内部溶液中过量的PIP 2阻止，而不是被内部Ca 2+缓冲或PKC抑制，这表明该机制是由于PLC的G-蛋白偶联受体刺激导致内源性PIP 2的消耗。因此，HERG K+通道的动态调节可以通过受体介导的PIP 2浓度变化来实现。
Autonomic stimulation controls heart rate and myocardial excitability and may underlie the precipitation of both acquired and hereditary arrhythmias. Changes in phosphatidyl inositol bisphosphate (PIP2) concentration results from activation of several muscarinic and adrenergic receptors. We sought to investigate whether PIP-2 changes could alter HERG K+ channel activity in a manner similar to that seen with inward rectifier channels. PIP2 (10 mu mol/L) internally dialyzed increased the K+ current amplitude and shifted the voltage-dependence of activation in a hyperpolarizing direction. Elevated PIP2 accelerated activation and slowed inactivation kinetics. When 10 mu mol/L PIP2 was applied to excised patches. no significant change in single channel conductance occurred, indicating that PIP2-dependent effects were primarily due to altered channel gating. PIP2 significantly attenuated the run-down of HERG channel activity that we normally observe after patch excision, suggesting that channel run-down is due, in part, to membrane depletion of PIP2. Inclusion of a neutralizing anti-PIP2 monoclonal antibody in whole cell pipette solution produced the opposite effects of PIP2. The physiological relevance of PIP2-HERG interactions is supported by our finding that phenylephrine reduced the K+ current density in cells coexpressing alpha 1A-receptor and HERG. The effects, of a-adrenergic stimulation, however, were prevented by excess PIP2 in internal solutions but not by internal Ca2+ buffering nor PKC inhibition, suggesting that the mechanism is due to G-protein-coupled receptor stimulation of PLC resulting in the consumption of endogenous PIP2. Thus, dynamic regulation of HERG K+ channels may be achieved via receptor-mediated changes in PIP2 concentrations.