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

细胞类型特异性P/Q型通道功能剖析

基本信息

批准号：
170834189
负责人：
Professor Dr. Stefan Herlitze
金额：
--
依托单位：
Lehrstuhl für Allgemeine Zoologie und Neurobiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/170834189?language=en
关键词：
Dissection cell type specific channel

项目摘要

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.

电压门控性钙通道介导神经元亚细胞内电压依赖性钙内流，触发神经递质释放、树突状细胞动作电位和兴奋-转录偶联等多种过程。由于其对细胞和系统功能的重要性，电压门控Ca 2+通道是用于治疗包括癫痫、疼痛、高血压、中风和偏头痛的几种主要疾病的治疗靶点。几个尚未解决的基本问题是Ca 2+通道如何靶向合适的细胞区室，以及Ca 2+通道存在细胞类型特异性功能。为了了解小鼠中的Ca 2+通道靶向和功能，我们创建并目前表征小鼠，其中P/Q型通道（脑中的主要电压门控Ca 2+通道之一）可以通过荧光标签可视化，并且可以在活小鼠中以时间、组织和细胞类型特异性方式缺失。我们将使用这些小鼠来剖析P/Q型通道的细胞/神经元类型特异性作用，这些作用是动物行为和疾病过程的基础，与P/Q型通道在多巴胺能系统中的表达有关。这项研究将揭示突触传递和树突状Ca 2+信号如何直接控制多巴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5-羟色胺释放和P/Q型通道之间建立功能性联系。这一点很重要，因为P/Q型通道突变会导致人类偏头痛，而偏头痛患者在偏头痛发作期间血清素水平较低。