Slowly Inactivating K+ Channels in Pyramidal Neurons

缓慢失活锥体神经元中的 K 通道

• 批准号: 6703733
• 负责人: Robert C Foehring
• 金额: $ 30.32万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6703733
• 关键词: electrophysiology; epilepsy; gene expression; genetically modified animals; immunocytochemistry; infrared microscopy; laboratory mouse; laboratory rat; neocortex; neurons; neurophysiology; polymerase chain reaction; potassium channel; pyramidal cells; somesthetic sensory cortex; synapses; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): Voltage-gated potassium currents play a crucial role in controlling neuronal excitability and sculpting patterns of neuronal activity. Consistent with these roles, K+ channels are exceptionally diverse. This diversity comes in part, from multiple genes, post-translational mechanisms, and heteromeric co-assembly of subunits. Recent molecular work has documented the diversity of subunits and has revealed some of the rules governing the association of subunit types. Studies in expression systems have demonstrated the biophysical and pharmacological properties of defined channel types. Relatively little is known about the composition of K+ channels in native membranes. The division of labor between the various K+ channel types in individual cells is also incompletely understood. Firing of regular-spiking (RS) pyramidal neurons in neocortex is characterized by relatively broad spikes, modest fAHPs, complex subthreshold integration, and rhythmic, repetitive firing with spike-frequency adaptation (SFA). In vivo studies indicate that the characteristic firing pattern of RS cells is integral to their functions in local circuit processing. Previous work by others and ourselves indicate that neocortical pyramidal cells express several K+ currents which regulate excitability. In particular, there is a diversity of slowly inactivating currents. This proposal is to (1) characterize the slowly-inactivating voltage-gated K+ currents and channel subunits in layer II/III pyramidal neurons from rat somatosensory cortex, (2) determine the relationship between particular channel subunits and macroscopic K+ currents, and (3) determine the mechanisms by which voltage-gated K+ currents regulate the RS firing pattern. These data are essential for understanding how pyramidal cells integrate synaptic inputs into spike trains, a process underlying cortical output. This work will also provide insights into abnormal cortical excitability and disease processes, such as epilepsy, as well as provide knowledge of the substrate for modulation by transmitters.

描述（由申请人提供）：电压门控钾电流在控制神经元兴奋性和塑造神经元活动模式方面发挥着至关重要的作用。与这些角色相一致，K+ 渠道异常多样化。这种多样性部分来自多个基因、翻译后机制和亚基的异聚共组装。最近的分子工作记录了亚基的多样性，并揭示了一些控制亚基类型关联的规则。表达系统的研究已经证明了特定通道类型的生物物理和药理学特性。关于天然膜中 K+ 通道的组成知之甚少。单个细胞中各种 K+ 通道类型之间的分工也不完全清楚。新皮质中规则尖峰（RS）锥体神经元放电的特点是相对较宽的尖峰、适度的 fAHP、复杂的阈下整合以及具有尖峰频率适应（SFA）的有节奏的重复放电。体内研究表明，RS 细胞的特征放电模式是其局部电路处理功能不可或缺的一部分。其他人和我们自己之前的工作表明，新皮质锥体细胞表达多种调节兴奋性的 K+ 电流。特别是，存在多种缓慢失活的电流。该提议旨在 (1) 表征大鼠体感皮层 II/III 层锥体神经元中缓慢失活的电压门控 K+ 电流和通道亚基，(2) 确定特定通道亚基与宏观 K+ 电流之间的关系，以及 (3 ）确定电压门控 K+ 电流调节 RS 放电模式的机制。这些数据对于理解锥体细胞如何将突触输入整合到尖峰序列（皮层输出的基础过程）中至关重要。这项工作还将提供对异常皮质兴奋性和疾病过程（例如癫痫）的见解，并提供有关递质调制底物的知识。