Instantaneous current and inactivation in HCN channels

超极化激活的“起搏器”电流对于哺乳动物心脏和大脑的节律性放电非常重要。这一提议提出了起搏电流的两个以前未描述的特征，（1）电压无关的瞬时电流，和（2）哺乳动物电流的失活。负责这两个电流特性的分子机制将通过分子生物学、化学修饰和膜片钳电生理学的组合在异源表达的起搏通道中进行实验探索。瞬时电流的存在表明背景电流伴随着心脏和大脑中起搏通道的表达，并提出了在其他离子通道中是否存在类似机制的问题。哺乳动物起搏电流中存在cAMP依赖性失活，并被细胞内因素改变的假说提示了这些电流调节的新机制。确定哺乳动物起搏电流的瞬时电流和/或失活的分子机制将促进我们对心脏和大脑中自发节律活动的控制和调节的理解。这些通道行为的描述也可能为开发作用于起搏通道的状态依赖性药理学试剂提供机会。

Hyperpolarization-activated "pacemaker" currents are important for rhythmic firing in the mammalian heart and brain. This proposal addresses two previously undescribed features of pacemaker currents, (1) a voltage-independent instantaneous current, and (2) inactivation of mammalian currents. The molecular mechanisms responsible for these two current properties will be probed experimentally in heterologously- expressed pacemaker channels by a combination of molecular biology, chemical modification, and patch clamp electrophysiology. The presence of an instantaneous current would suggest that a background current accompanies expression of pacemaker channels in the heart and brain, and would raise the question of whether similar mechanisms exist in other ion channels. The hypotheses that cAMP-dependent inactivation existing in mammalian pacemarker currents and is altered by intracellular factors suggest a novel mechanism for modulation of these currents. Determination of the molecular mechanism for an instantaneous current and/or inactivation of mammalian pacemaker currents would advance our understanding of the control and modulation of spontaneous rhythmic activity in the heart and brain. Description of these channel behavior may also present opportunities for development of state-dependent pharmacological agents that act on pacemaker channels.