Electrophysiology of peripheral nerve sodium channels

周围神经钠通道的电生理学

• 批准号: 7578326
• 负责人: MICHAEL E O'LEARY
• 金额: $ 24.21万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578326
• 关键词: Adverse effects; American; C Fiber; Caliber; Cell Line; Cells; Chemicals; Chimera organism; Cloning; Complement; Cultured Cells; Data; Defect; Dependence; Electrophysiology (science); Esthesia; Functional disorder; Ganglia; Gated Ion Channel; Healthcare; In Vitro; Kinetics; Lesion; Ligands; Link; Mammalian Cell; Mechanics; Membrane; Modification; Molecular; Mutagenesis; Myxoid cyst; N-terminal; Narcotics; Nerve Fibers; Nervous system structure; Neuraxis; Neurons; Nociception; Nociceptors; Oocytes; Organelles; Pain; Pain management; Pathway interactions; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Physiology; Play; Property; Protein Isoforms; Proteins; Regulation; Research; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Sodium Channel; Spinal Ganglia; Structure-Activity Relationship; Syndrome; System; Tetrodotoxin; Tissues; Xenopus oocyte; addiction; afferent nerve; chronic neuropathic pain; chronic pain; cost; electrical property; extracellular; in vivo; inhibitor/antagonist; insight; nerve injury; neuronal cell body; neuronal excitability; painful neuropathy; patch clamp; programs; protein folding; reconstitution; research study; trafficking; voltage

DESCRIPTION (provided by applicant): Studies indicate that approximately 30% of Americans suffer from chronic pain conditions annually resulting in >100 billion dollars in health-care related costs. Currently prescribed narcotics used to treat severe pain have significant side effects and are prone to physical addiction. In addition, these drugs are ineffective in treating neuropathic pain resulting from lesion or dysfunction of the nervous system. The unmyelinated C fibers of peripheral nerve transmit painful sensation (nociception) from the sensory nerve terminals located in tissues to the central nervous system. These slowly conducting nerve fibers are the initial link in the nociception pathway and are therefore important targets of pain therapy. Nociceptors express a combination of ligand- and voltage-gated ion channels that enable these neurons to respond to peripheral tissue damage and nerve injury. The cell bodies of nociceptors are located in the dorsal root ganglion (DRG) and express a unique Na current that is resistant to tetrodotoxin (TTX), a prototypical inhibitor of sodium channels. This TTX-resistant Na current has been the focus of intense research because of its purported role in chronic and neuropathic pain syndromes. Two Na channels (Nav1.7, Nav1.8) have been cloned from peripheral nerve that display properties similar to the TTX-sensitive and TTX-resistant currents expressed in DRG nociceptors. The proposed studies will characterize the biophysical properties of the Nav1.7 and Nav1.8 channels heterologously expressed in a mammalian cell line. In vivo, these Na channels are associated with one or more accessory beta subunits that regulate the expression and voltage-dependent gating of the channels. The proposed studies will use single-cell RT-PCR to identify the beta subunits that are expressed in the pain-sensing nociceptors of the DRG. The effects of the identified beta subunits on the kinetics and voltage-dependent gating of heterologously expressed peripheral nerve Na channels (Nav1.7, Nav1.8) will be investigated. Overall, our proposed studies will provide new insights into the Na channels and regulatory subunits that govern the electrical excitability of nociceptive neurons.

描述（由申请人提供）：研究表明，大约 30% 的美国人每年患有慢性疼痛，导致医疗保健相关费用超过 1000 亿美元。目前用于治疗严重疼痛的麻醉药物具有显着的副作用，并且容易导致身体成瘾。此外，这些药物对于治疗由神经系统损伤或功能障碍引起的神经性疼痛无效。周围神经的无髓鞘 C 纤维将疼痛感（伤害感受）从组织中的感觉神经末梢传递到中枢神经系统。这些缓慢传导的神经纤维是伤害感受通路的初始环节，因此是疼痛治疗的重要目标。伤害感受器表达配体门控离子通道和电压门控离子通道的组合，使这些神经元能够对周围组织损伤和神经损伤做出反应。伤害感受器的细胞体位于背根神经节 (DRG) 中，表达独特的钠电流，可抵抗河豚毒素 (TTX)，河豚毒素是一种典型的钠通道抑制剂。这种 TTX 抗性钠电流因其在慢性和神经性疼痛综合征中的作用而成为深入研究的焦点。已从周围神经克隆了两个 Na 通道（Nav1.7、Nav1.8），其表现出与 DRG 伤害感受器中表达的 TTX 敏感和 TTX 抗性电流相似的特性。拟议的研究将表征哺乳动物细胞系中异源表达的 Nav1.7 和 Nav1.8 通道的生物物理特性。在体内，这些 Na 通道与一个或多个辅助 β 亚基相关，调节通道的表达和电压依赖性门控。拟议的研究将使用单细胞 RT-PCR 来鉴定在 DRG 疼痛感知伤害感受器中表达的 β 亚基。将研究已鉴定的 β 亚基对异源表达的周围神经 Na 通道（Nav1.7、Nav1.8）的动力学和电压依赖性门控的影响。总的来说，我们提出的研究将为控制伤害性神经元电兴奋性的 Na 通道和调节亚基提供新的见解。