Sodium channel control of neuronal excitability

电压门控钠通道(VGSCs)对动作电位的产生至关重要。此外，药物 直接靶向VGSC被广泛用于治疗常见疾病，如疼痛、情绪障碍、肌肉 痉挛、癫痫和心律失常。然而，由于分布广泛，副作用也会出现。 以及VGSC各亚型对阻滞剂的交叉敏感性。此外，这些药物并不是 完全有效，强调了对针对VGSC的新药的大量需求。这促使我们 识别和描述调节VGSC功能的新机制。电压的调节- 门控离子通道功能是调节神经元信号和脑功能的重要途径， G蛋白偶联受体(GPCRs)是内源性信号转导机制的重要组成部分 这是通过它发生的。然而，与其他离子通道不同的是，VGSC被认为是相对 对GPCR信号的调节不敏感。我们最近发现了一种途径，它受 已知的与钙敏感受体(CaSR)相互作用的试剂。这条途径广泛存在，存在于 绝大多数新皮质神经元，并且足够强大，足以完全和可逆地阻断VGSC电流 当最大限度地刺激时。这种新颖的、动态的信号通路被定位为实质上调制 神经元兴奋性和脑功能。对潜在机制的详细了解对以下方面至关重要 了解它的诸多影响。这项提案的目标是确定CASR调节器如何调节 VGSCs。使用电生理学和无偏生化方法的组合，我们将识别 介导VGSC电流抑制的受体，测定不同VGSC对阻断的相对敏感性 并确定该通路是否对神经末梢和胞体的动作电位有不同的调节作用。 这些特定的目标将检验这样一个假设，即CASR调节器通过VGSC的作用代表着重要的新的 调节神经元兴奋性的途径。我们非常适合执行这个项目，因为我们的 初步数据和专业知识。我们的理论基础是，对一部小说和 流行受体(S)及其下游途径将有助于我们理解一种流行的和潜在的 强大的神经生物信号通路。成功完成这些具体目标将成为新的特点 药物靶点，并最终将导致新的治疗方法，以改善对疼痛，癫痫，肌肉痉挛， 还有心律失常。

Voltage-gated sodium channels (VGSCs) are essential for action potential generation. Furthermore, drugs that directly target VGSCs are widely used to treat common diseases, such as pain, mood disorders, muscle spasms, seizures, and cardiac arrhythmias. However, side effects arise because of the widespread distribution of VGSCs and cross-sensitivity of the various VGSC subtypes to blockers. In addition, these drugs are not completely effective, underlining a substantial need for new drugs that target VGSCs. This has motivated us to identify and characterize new mechanisms by which VGSC function can be regulated. Regulation of voltage- gated ion channel function is an important pathway by which neuronal signaling and brain function is regulated, and G-protein coupled receptors (GPCRs) form a major element of the endogenous transduction mechanisms by which this occurs. However, unlike other ion channels, VGSCs have been assumed to be relatively insensitive to modulation by GPCR signaling. We have recently identified a pathway that is modulated by agents known to interact with the CaSR (calcium-sensing receptor). This pathway is widespread, present in the vast majority of neocortical neurons, and strong enough to completely and reversibly block VGSC currents when maximally stimulated. This novel, dynamic signaling pathway is positioned to substantially modulate neuronal excitability and brain function. Detailed knowledge about the underlying mechanisms is crucial to understand its many effects. The objectives of this proposal are to determine how CaSR modulators regulate VGSCs. Using a combination of electrophysiology and unbiased biochemical approaches we will identify the receptors mediating the inhibition of VGSC currents, measure the relative sensitivity to block of different VGSC isoforms, and determine if the pathway differentially regulates action potentials at nerve terminals and soma. These specific aims will test the hypothesis that CaSR modulators actions via VGSCs represent important new pathways for modulating neuronal excitability. We are ideally suited to perform this project because of our preliminary data and expertise. Our rationale is that the identification and characterization of a novel and prevalent receptor(s) and downstream pathway will facilitate our understanding of a prevalent and potentially powerful neurobiological signaling pathway. Successful completion of these specific aims will characterize new drug targets and eventually will lead to new therapeutics to improve control of pain, seizures, muscle spasm, and arrhythmias.