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。与这些角色相一致，K+通道异常多样化。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。最近的分子工作已经记录了亚基的多样性，并揭示了一些规则的亚基类型的协会。在表达系统中的研究已经证明了定义的通道类型的生物物理和药理学特性。对天然膜中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。新皮层中规则发放（RS）锥体神经元的放电特征为相对宽的发放、适度的fAHPs、复杂的阈下整合以及具有发放频率适应（SFA）的节律性重复放电。体内研究表明，RS细胞的特征性放电模式与其在局部电路处理中的功能是不可或缺的。前人和我们的工作表明，新皮层锥体细胞表达几种调节兴奋性的K+电流。特别是，有各种各样的缓慢失活电流。本研究的目的是：（1）鉴定大鼠体感皮层第II/III层锥体神经元的慢失活电压门控性K ~+电流和通道亚单位，（2）确定特定通道亚单位与宏观K ~+电流之间的关系，（3）确定电压门控性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成锋电位序列是必不可少的，这是一个潜在的皮层输出过程。这项工作还将提供对异常皮层兴奋性和疾病过程（如癫痫）的深入了解，并提供有关递质调制底物的知识。

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.