Slowly Inactivating K+ Channels in Pyramidal Neurons

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起着至关重要的作用。与这些角色一致的是，K+通道异常多样。这种多样性部分来自于多个基因、翻译后机制和亚基的异构体共同组装。最近的分子研究记录了亚基的多样性，并揭示了一些支配亚基类型关联的规则。对表达系统的研究已经证明了确定的通道类型的生物物理和药理学特性。对天然细胞膜中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。大脑皮层规则峰(RS)锥体神经元的放电具有相对宽广的棘波、适度的fAHP、复杂的阈值下整合、节律性重复放电和峰频适应(SFA)的特点。体内研究表明，RS细胞的特征放电模式对于它们在局部电路处理中的功能是不可或缺的。其他人和我们之前的工作表明，新皮质锥体细胞表达几种调节兴奋性的K+电流。特别是，存在着多种缓慢失活的电流。本研究的目的是：(1)研究大鼠体感皮层II/III层锥体神经元缓慢失活电压门控K+电流和通道亚基的特征；(2)确定具体通道亚基与宏观K+电流的关系；(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棘波序列中是至关重要的，这是皮层输出的一个过程。这项工作还将提供对大脑皮质异常兴奋性和疾病过程(如癫痫)的洞察，并提供有关递质调制的底物的知识。

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.