Regulation of Neuronal Calcium Channels

描述（由申请人提供）：电压门控Cav通道介导基因转录和神经传递所需的活性依赖性Ca2+信号。Ca2+依赖性失活和促进（分别为CDI和CDF）允许Cav通道根据神经元活动调节Ca2+内流，从而微调控制神经元兴奋性和突触可塑性的Ca2+信号。提出的研究的基本原理是，定义Cav通道如何产生和维持Ca2+信号将回答长期存在的问题，关于神经元中Cav通道的异质特性，并使新的机制探究特定Cav通道在协调神经系统正常发育和功能中的作用。拟议研究的预期结果是：建立calretinin作为包括Cav2.1在内的效应物的动态调节剂的新作用（Aim 1）；阐明了神经元Cav1 l型电流的“持久”特性和功能影响的机制（目的2）。我们相信，拟议的研究将产生持久和积极的影响：它将确定的Cav通道调节机制将可能促进神经和神经精神疾病的新疗法的发展，这些疾病是由神经元Ca2+信号失调引起的。

DESCRIPTION (provided by applicant): Voltage-gated Cav channels mediate activity-dependent Ca2+ signals required for gene transcription and neurotransmission. Ca2+-dependent inactivation and facilitation (CDI and CDF, respectively) allow Cav channels to adjust Ca2+ influx according to neuronal activity, thereby fine-tuning Ca2+ signals that control neuronal excitability and synaptic plasticity. The rationale for the proposed research is that defining how Cav channels generate and maintain Ca2+ signals will answer longstanding questions regarding the heterogeneous properties of Cav channels in neurons and enable new mechanistic inquiries into the roles of specific Cav channels in orchestrating the normal development and function of the nervous system. The expected outcomes of the proposed research are: establishment of a new role for calretinin as a dynamic regulator of effectors including Cav2.1 (Aim 1); and elucidation of a mechanism responsible for the "long-lasting" properties and functional impact of neuronal Cav1 L-type currents (Aim 2). We believe that the proposed research will make a lasting and positive impact: the Cav channel regulatory mechanisms it will define will likely facilitate the development of novel therapeutics for neurological and neuropsychiatric disorders resulting from dysregulation of neuronal Ca2+ signals.