Sodium channel control of neuronal excitability

钠通道控制神经元兴奋性

• 批准号: 10394713
• 负责人: Stephen M Smith
• 金额: $ 20.56万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394713
• 关键词: Action Potentials; Acute; Affect; Agonist; Arrhythmia; Azides; Biochemical; Biological Assay; Biophysical Process; Biophysics; Brain; Calcium-Sensing Receptors; Cannabinoids; Cellular biology; Clinical; Collaborations; Complex; Coupled; Crosslinker; Cyclic AMP; Data; Disease; Dose; Electrophysiology (science); Elements; Endocannabinoids; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Generations; Gilles de la Tourette syndrome; Glycerol; Goals; Huntington Disease; Hypercalcemia; Ion Channel; Ion Channel Gating; Kidney Failure; Knowledge; Lead; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Molecular; Mood Disorders; Mus; Muscle Cells; Muscle Spasticity; Muscle function; Nerve; Neurobiology; Neurons; Neuropathy; Pain; Pain management; Paralysed; Patch-Clamp Techniques; Pathway interactions; Patients; Pattern; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Phosphatidylinositols; Physiological; Positioning Attribute; Protein Biochemistry; Protein Isoforms; Proteins; Psychotropic Drugs; Regulation; Resolution; Second Messenger Systems; Seizures; Signal Pathway; Signal Transduction; Slice; Sodium Channel; Spasm; Streptavidin; System; Testing; United States National Institutes of Health; Work; anandamide; antagonist; base; chemoproteomics; cinacalcet; crosslink; design; experimental study; improved; innovation; inorganic phosphate; interest; knock-down; live cell imaging; neocortical; neuronal cell body; neuronal excitability; neurotransmission; new therapeutic target; novel; novel therapeutics; periodic paralysis; receptor; screening program; sensor; side effect; small hairpin RNA; tool; ultraviolet irradiation; voltage; voltage gated channel

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.

电压门控钠通道（VGSC）对于动作电位产生至关重要。此外，毒品 直接靶向VGSC被广泛用于治疗常见疾病，例如疼痛，情绪障碍，肌肉 痉挛，癫痫发作和心律不齐。但是，由于广泛的分布而产生副作用 VGSC的VGSC和各种VGSC子类型对阻滞剂的交叉敏感性。此外，这些药物不是 完全有效，强调了针对VGSC的新药物的巨大需求。这激发了我们 识别并表征可以调节VGSC函数的新机制。调节电压 门控离子通道功能是一个重要的途径，通过调节神经元信号传导和大脑功能， 和G蛋白偶联受体（GPCR）构成内源性转导机制的主要元素 发生这种情况。但是，与其他离子通道不同，VGSC被认为是相对的 GPCR信号传导对调制不敏感。我们最近确定了一个由 已知与CASR相互作用的药物（钙感应受体）。该途径很普遍，存在于 绝大多数新皮质神经元，足够强，可以完全和可逆地阻止VGSC电流 当最大刺激时。这个小说的动态信号通路定位为基本调制 神经元兴奋性和大脑功能。关于基本机制的详细知识对 了解其许多效果。该提案的目标是确定CASR调制器如何调节 VGSC。结合电生理学和无偏生化方法，我们将确定 介导VGSC电流抑制的受体，测量对不同VGSC块的相对灵敏度 同工型，并确定该途径是否在神经末端和SOMA上差异调节作用电位。 这些具体目的将检验CASR调节器通过VGSC的行动代表重要新的假设 调节神经元兴奋性的途径。我们非常适合执行该项目，因为我们 初步数据和专业知识。我们的理由是，小说的识别和特征 普遍的受体和下游途径将有助于我们对普遍存在的理解 强大的神经生物学信号通路。这些特定目标的成功完成将表征新的 药物靶标，最终将导致新的治疗剂，以改善对疼痛，癫痫发作，肌肉痉挛的控制， 和心律不齐。