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的钙信号。CA2依赖的失活和促进(分别为CDI和CDF)允许Cav通道根据神经元的活动来调节钙内流，从而微调控制神经元兴奋性和突触可塑性的钙信号。这项研究的基本原理是，定义Cav通道如何产生和维持钙信号，将回答长期以来关于Cav通道在神经元中的异质性的问题，并使新的机制探讨特定的Cav通道在协调神经系统的正常发育和功能中所起的作用。拟议研究的预期结果是：确立Calretinin作为包括Cav2.1在内的效应器的动态调节的新角色(目标1)；以及阐明负责神经元Cav1 L型电流的“持久”特性和功能影响的机制(目标2)。我们相信，这项拟议的研究将产生持久和积极的影响：它将定义的Cav通道调节机制可能会促进由神经元钙信号调节失调引起的神经和神经精神疾病的新疗法的开发。

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.