MOLECULAR PHYSIOLOGY OF ALPHA1 RECEPTORS AND POTASSIUM CHANNELS

刺激α/1-肾上腺素能受体增加动作电位 持续时间和心肌细胞的收缩力，通过几个 细胞功能的改变。一个重要的机制是 抑制钾通道。虽然电生理 钾通道的α-1-肾上腺素能抑制的描述是 十多年前报道，在理解这个系统方面取得了进一步的进展， 与我们对其他神经调节机制的理解相比， 系统.在很大程度上，这种有限的进展是由于缺乏 适当的模型系统，其中可以 联合起来直接解决这个问题。 我们建议研究α/1-肾上腺素能调节两种钾离子 在心肌细胞中表达的通道：内向整流器 通道（I/k1）和瞬时外向通道（I/to）。我们将使用两个 分析抑制机制的细胞系统：a 异源表达系统和转染的培养肌细胞系统。 最重要的是，关于α/1-肾上腺素能神经递质的性质的假设 将研究在这些细胞中表达的钾通道的调节 结合分子、电生理和蛋白质 化学接近。 目前还不确定α/1-肾上腺素能通路如何调节关键的 效应分子如心肌细胞中的钾通道。这 在确定α-肾上腺素能对 复极（影响动作电位持续时间的异质性， 心律失常的易感性）和脉冲启动（重要 关于生育）。分子机制的确定 参与是必不可少的，以发展一个了解如何 交感神经系统及其神经递质可以触发 心律失常

Stimulation of alpha/1-adrenergic receptors increases the action potential duration and the force of contraction in cardiac myocytes via several modifications of cellular function. One important mechanism is the inhibition of potassium channels. Although the electrophysiological description of alpha-1-adrenergic inhibition of potassium channels was reported over a decade ago, further progress in understanding this system has lagged in comparison to our understanding of other neuromodulatory systems. In large part this limited progress has been due to the lack of suitable model systems in which a range of technical approaches can be combined to direct address this problem. We propose to study alpha/1-adrenergic modulation of two potassium channels that are expressed in cardiac myocytes: the inward rectifier channel (I/k1) and the transient outward channel (I/to). We will use two cell systems in which to analyze the mechanisms of inhibition: a heterologous expression system and a transfected cultured myocytes system. Most importantly, hypotheses concerning the nature of alpha/1-adrenergic modulation of potassium channels expressed in these cells will be studied using a combination of molecular, electrophysiological and protein chemistry approaches. It is currently uncertain how the alpha/1-adrenergic pathway modulates key effector molecules such as potassium channels in cardiac myocytes. This pathway in important in determining alpha-adrenergic effects on repolarization (affect heterogeneity of action potential duration and susceptibility to arrhythmias) and impulse initiation (important concerning arrhythmogenesis). Determination of the molecular mechanisms involved is essential to developing an understanding for how the sympathetic nervous system and its neurotransmitters can act to trigger cardiac arrhythmias.