Dissection of cell-type specific P/Q-type channel function

电压门控Ca2+通道介导电压依赖性Ca2+内流在神经元的亚细胞区室，触发多种过程，如神经递质释放，树突动作电位和兴奋-转录耦联。由于它们对细胞和系统功能的重要性，电压门控Ca2+通道是治疗几种主要疾病的治疗靶点，包括癫痫、疼痛、高血压、中风和偏头痛。仍未解决的几个基本问题是Ca2+通道如何靶向适当的细胞区室以及Ca2+通道存在细胞类型特异性功能。为了了解Ca2+通道在小鼠中的靶向性和功能，我们创建并目前表征了小鼠，其中P/ q型通道（大脑中主要电压门控Ca2+通道之一）可以通过荧光标记可视化，并且可以在活小鼠中以时间，组织和细胞类型特异性的方式删除。我们将使用这些小鼠来解剖P/ q型通道在动物行为和疾病过程中与血清素能系统中P/ q型通道表达相关的细胞/神经元类型特异性作用。该研究将揭示突触传递和树突Ca2+信号如何直接控制5 -羟色胺能神经元的动作电位放电和5 -羟色胺释放。因此，我们将在血清素释放和P/ q型通道之间建立功能联系。这很重要，因为P/ q型通道突变导致人类偏头痛，偏头痛患者在偏头痛发作期间血清素水平较低。

Voltage gated Ca2+ channels mediate voltage-dependent Ca2+ influx in subcellular compartments of neurons, triggering such diverse processes as neurotransmitter release, dendritic action potentials and excitation-transcription coupling. Because of their importance for cellular and system function voltage gated Ca2+ channels are therapeutic targets for the treatment of several major diseases including epilepsy, pain, hypertension, stroke and migraine. Several fundamental questions that remain unsolved are how Ca2+ channels are targeted to the appropriate cellular compartments and do cell-type specific functions of the Ca2+ channel exist. In order to understand Ca2+ channel targeting and function in mice, we created and currently characterize mice, where the P/Q-type channel (one of the main voltage gated Ca2+ channels in the brain) can be visualized via a fluorescent tag and can be deleted in a temporal, tissue and cell-type specific manner in the living mice. We will use these mice to dissect the cell/neuron-type specific role of the P/Q-type channels underlying animal behavior and disease processes related to P/Q-type channel expression in the serotonergic system. The research will reveal how synaptic transmission and dendritic Ca2+ signals control action potential firing and serotonin release directly in serotonergic neurons. Thus, we will make a functional connection between serotonin release and P/Q-type channels. This is important because P/Q-type channel mutations cause migraine in humans and migraine patients have low serotonin levels during migraine attacks.