Ion channels and their functions at the node of Ranvier of mammalian somatosensory afferent fibers

兰维尔结节是感觉、运动和有髓神经纤维上高度特化的轴突区域。 通过跳跃(拉丁语中的Leap)传导来传播动作电位的中枢神经系统。 通过兰维尔结点的跳跃传导确保了及时的感觉和运动反应以及准确的信号 中枢神经系统的处理。许多神经系统疾病影响兰维尔结节以损害跳跃。 导致运动障碍的传导，如瘫痪和感觉功能障碍，如疼痛、麻木、 以及其他不正常的感觉。对哺乳动物兰维尔结节离子通道及其功能的认识 是充分理解生理和病理条件下跳跃传导的关键，并且 用于这些感觉和运动障碍的潜在治疗。这个项目的总体目标是研究离子 在哺乳动物兰维尔结节确保动作电位跳跃传导的通道机制。 我们最近发展了一种原位膜片钳记录技术。 大鼠的体感传入纤维。在初步研究中，我们发现兰维尔节点表达 令人惊讶的高水平的两孔结构域钾通道(K2P通道)，一个独特的离子家族 结构性开放的通道，其在动作电位和神经传导中的作用 此前并不为人所知。在功能上，我们的初步研究强烈表明K2P通道是关键 用于保护哺乳动物有髓躯体感觉传入纤维中跳跃传导的分子。在这 应用，我们将使用原位膜片钳记录技术结合药理学、基因 击倒，和免疫化学方法，以实现以下具体目标。目标1.描述 K2P通道及其在大鼠体感觉Ranvier结点的分子定位 传入纤维。在这个目标中，我们将在Ranvier的结点确定K2P通道子类型，并分析它们的 药理和单通道特性。目的2.研究K2P通道在安全保护中的具体作用 大鼠体感觉传入纤维Ranvier结处的跳跃性传导。这一目标将阐明 兰维尔结点的K2P通道在快速动作电位复极和心肌梗死中起关键作用。 确保高速和高频跳跃传导。目的3.阐明K2P通道在 兰维尔结节在大鼠体感跳跃性温度传导中起关键作用 传入纤维。这一目标将检验兰维尔结点的K2P通道是高度热的这一想法 敏感性，这是一个决定因素，控制跳跃传导的速度和保真度不同 温度。这一目的说明，影响K2P通道活性的生物因素将高度影响 有髓神经纤维的跳跃性传导。这3个目标的完成将阐明一种新的离子通道 确保跳跃传导的机制，这可能对感觉和运动障碍有影响 兰维尔交界处跳跃性传导受损。

Nodes of Ranvier are highly specialized axonal regions on myelinated nerve fibers of sensory, motor and central nervous systems where action potentials are propagated by saltatory (leap in Latin word) conduction. Saltatory conduction through nodes of Ranvier ensures timely sensory and motor responses and precise signal processing in the CNS. A number of neurological diseases affect nodes of Ranvier to impair saltatory conduction leading to motor disorders, such as paralysis and sensory dysfunctions, such as pain, numbness, and other abnormal sensations. Knowledge of ion channels and their functions at mammalian nodes of Ranvier is a key to fully understanding saltatory conduction under both physiological and pathological conditions, and for potential treatments of those sensory and motor disorders. The overall goal of this project is to study ion channel mechanisms for securing saltatory conduction of action potentials at mammalian nodes of Ranvier. We have recently developed the in situ patch-clamp recording technique for nodes of Ranvier in somatosensory afferent fibers of rats. In the preliminary studies we have found that nodes of Ranvier express surprisingly high levels of the two-pore domain potassium channels (K2P channels), a unique family of ion channels that constitutively open, and the function of which, in action potentials, as well as in nerve conduction was previously unknown. Functionally, our preliminary studies strongly suggest that K2P channels are key molecules for securing saltatory conduction in myelinated somatosensory afferent fibers of mammals. In this application, we will use the in situ patch-clamp recording technique in conjunction with pharmacology, gene knockdown, and immunochemistry approaches to achieve the following specific aims. Aim 1. Characterize K2P channels and elucidate their molecular identities at the node of Ranvier of rat somatosensory afferent fibers. In this aim we will pin down K2P channel subtypes at the node of Ranvier and profile their pharmacological and single channel properties. Aim 2. Study specific roles of K2P channels in securing saltatory conduction at the node of Ranvier of rat somatosensory afferent fibers. This aim will elucidate that the K2P channels at the node of Ranvier play a key role in rapid action potential repolarization and in securing high speed and high frequency saltatory conduction. Aim 3. Elucidate that K2P channels at the node of Ranvier play a key role in temperature-dependent saltatory conduction on rat somatosensory afferent fibers. This aim will test the idea that K2P channels at the node of Ranvier are highly thermal sensitive, which is a determinant factor controlling the velocity and fidelity of saltatory conduction at different temperatures. This aim exemplifies that biological factors affecting K2P channel activity will highly impact saltatory conductions in myelinated nerve fibers. Completion of the 3 Aims will elucidate a novel ion channel mechanism that secures saltatory conduction, which may have implications in sensory and motor disorders with impaired saltatory conduction at the node of Ranvier.