Role of dimer formation in modulating neuronal sodium channel properties

二聚体形成在调节神经元钠通道特性中的作用

• 批准号: 10741033
• 负责人: THEODORE R CUMMINS
• 金额: $ 42.76万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741033
• 关键词: Action Potentials; Address; Ataxia; Biochemical; Biological Assay; Brain; Cells; Detection; Development; Disease; Ensure; Epilepsy; Future; Generations; Goals; Human; Investigation; Knowledge; Lead; Ligation; Link; Membrane; Molecular; Muscle; Muscle Cells; Mutation; Myotonia; Neurons; Pain; Pathologic; Pharmacology; Physiological; Property; Protein Isoforms; Proteins; Reporting; Research; Research Project Grants; Resistance; Role; SCN1A protein; SCN2A protein; SCN8A gene; Signal Transduction; Sodium; Sodium Channel; Specificity; Spinal Ganglia; System; TEV protease; Technology; Testing; Tetrodotoxin; Tobacco use; Variant; Work; autism spectrum disorder; design; design and construction; difopein; dimer; excitatory neuron; experimental study; inhibitory neuron; mutant; nervous system disorder; neuronal excitability; novel; protein protein interaction; sodium channel proteins; treatment strategy; voltage

Summary/Abstract Voltage-gated sodium channels are major contributors to the generation and propagation of action potentials in neurons and muscle. Changes in the properties of sodium currents can substantially alter the excitability of excitable cells. Indeed, sodium channel variants have been associated with a wide array of disorders of excitability, including pain, epilepsy, ataxias, autism, myotonias and arrythmias. A multitude of sodium channel disease mutations have been characterized. Many mutations can alter diverse sodium current properties and the observed changes can range from profound to subtle. Interestingly, although many mutations have dominant effects, the vast majority of characterizations have focused on isolated channel variants. Several recent studies suggest that some voltage-gated sodium channels can form dimers and that dimer formation may alter the impact of specific variants on sodium current properties. If dimer formation substantially alters sodium current properties and/or the physiological consequences of disease mutations, then investigations of the functional consequences of disease mutants in the presence of wild-type channels, other variants and even other isoforms may be needed to fully understand how specific channel isoforms and variants contribute to electrogenesis and different pathological conditions. We will investigate if dimer formation can result in changes in multiple properties, including activation, deactivation, fast inactivation, slow inactivation and persistent currents of Nav1.1 and Nav1.7 isoforms. Next, we will use Proximity Ligation Assays to examine the potential of dimer formation on brain isoforms in cell systems. Finally, we will examine potential consequences of dimer formation on Nav1.6 and Nav1.7 channel variants associated with pain expressed in dorsal root ganglion neurons to help determine if dimers can impact the properties of channels in a natural cell background. This exploratory research project targets several key gaps in our knowledge relating to the potential consequences of VGSC dimers. A fuller understanding of this phenomena could lead to a more complete understanding of channelopathies and possibly spur the development of novel treatment strategies.

总结/摘要 电压门控性钠通道是神经细胞动作电位产生和传播的主要贡献者。 神经元和肌肉。钠电流性质的改变可以显著改变神经元的兴奋性。 可兴奋细胞事实上，钠通道变异体与一系列广泛的代谢紊乱有关。 兴奋性，包括疼痛、癫痫、共济失调、自闭症、肌强直和心律失常。大量钠离子通道 疾病突变已被表征。许多突变可以改变不同的钠电流特性， 观察到的变化可以从深刻到微妙。有趣的是，尽管许多突变具有显性 尽管存在这些效应，但绝大多数表征都集中在孤立通道变体上。最近的几项研究 提示某些电压门控钠通道可以形成二聚体，而二聚体形成可能改变这种影响 钠电流特性的特殊变体。如果二聚体的形成实质上改变了钠电流的特性 和/或疾病突变的生理后果，然后研究功能后果， 在野生型通道存在的情况下，可能需要疾病突变体的其他变体甚至其他同种型 为了充分理解特定的通道亚型和变体如何有助于电发生和不同的 病理条件。我们将研究二聚体的形成是否会导致多种性质的变化， 包括Nav1.1的激活、失活、快速失活、缓慢失活和持续电流， Nav1.7同种型。接下来，我们将使用邻近连接试验来检查上二聚体形成的可能性 细胞系统中的脑同种型。最后，我们将研究Nav1.6上二聚体形成的潜在后果。 和Nav1.7通道变体与背根神经节神经元中表达的疼痛相关，以帮助确定 二聚体是否会影响天然细胞背景中通道的性质。这个探索性的研究项目 针对我们知识中与VGSC二聚体潜在后果相关的几个关键空白。更全面 对这种现象的理解可能会导致对通道病的更全面的理解， 刺激新的治疗策略的发展。