Instantaneous current and inactivation in HCN channels

超极化激活的“起搏器”电流对哺乳动物心脏和大脑的节律性放电很重要。这项建议解决了起搏器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。通过分子生物学、化学修饰和膜片钳电生理学相结合的方法，在异源表达的起搏器通道中，对导致这两种电流特性的分子机制进行实验探索。瞬时电流的存在表明起搏器通道在心脏和大脑中的表达伴随着背景电流，并提出了其他离子通道是否存在类似机制的问题。哺乳动物起搏电流中存在cAMP依赖失活的假说，并被细胞内因素改变，这为这些电流的调节提供了一种新的机制。瞬时电流和/或哺乳动物起搏器电流失活的分子机制的确定将促进我们对心脏和大脑自发节律活动的控制和调节的理解。对这些通道行为的描述也可能为作用于起搏器通道的状态依赖的药理学药物的开发提供机会。

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.