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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要/文摘