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、癫痫发作和心律失常。然而，由于广泛分布，会产生副作用 VGSC 的数量以及各种 VGSC 亚型对阻断剂的交叉敏感性。另外，这些药物不 完全有效，突显了对针对 VGSC 的新药的巨大需求。这激励我们 识别和表征可调节 VGSC 功能的新机制。电压调节- 门控离子通道功能是调节神经元信号传导和脑功能的重要途径， 和 G 蛋白偶联受体 (GPCR) 构成内源性转导机制的主要元素 从而发生这种情况。然而，与其他离子通道不同，VGSC 被认为是相对 对 GPCR 信号的调节不敏感。我们最近发现了一条受以下因素调节的途径 已知与 CaSR（钙敏感受体）相互作用的药物。该途径广泛存在于 绝大多数新皮质神经元，并且足够强大以完全且可逆地阻断 VGSC 电流 当受到最大刺激时。这种新颖的动态信号传导途径旨在显着调节 神经元兴奋性和脑功能。有关基本机制的详细了解对于 了解它的许多影响。该提案的目标是确定 CaSR 调节剂如何调节 VGSC。结合使用电生理学和公正的生化方法，我们将确定 介导 VGSC 电流抑制的受体，测量对不同 VGSC 阻断的相对敏感性 亚型，并确定该通路是否差异调节神经末梢和体细胞的动作电位。 这些具体目标将检验以下假设：CaSR 调节剂通过 VGSC 的作用代表了重要的新功能 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 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了解普遍的和潜在的 强大的神经生物学信号通路。成功完成这些具体目标将成为新的特征 药物靶向并最终将导致新的治疗方法来改善对疼痛、癫痫、肌肉痉挛的控制， 和心律失常。