L-type Ca2+ channel regulation of dendritic arborization

L型Ca2+通道对树突状树枝化的调控

• 批准号: 7110009
• 负责人: JOCELYN F KREY
• 金额: $ 4.68万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2009-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110009
• 关键词: autism; dendrites; electrical potential; emotions; gene mutation; mutant; nervous system disorder; neurons; play; role; syndrome

DESCRIPTION (provided by applicant): Dendrite growth is a key step in the development of neuronal circuitry and is perturbed in epilepsy, autism and other neurological diseases. Electrical activity regulates the development and plasticity of dendritic arbors by activating L-type voltage gated Ca2+ channels (LTCs). The goal of this proposal is to understand how LTCs regulate dendritic growth and arborization. To achieve this goal, we have developed a strategy that allows us to introduce mutant LTCs into neurons and to study how these exogenous channels regulate the dendritic arbor. Preliminary studies indicate that LTCs bearing a G406R mutation that causes the autistic disorder Timothy Syndrome (TS), are dramatically impaired in their ability to promote dendrite growth. I plan to characterize the defects of TS mutant LTCs and to investigate how other biophysical and biochemical features of LTCs affect the channel's ability to regulate the dendritic cytoskeleton. These studies will help elucidate the mechanisms by which electrical activity regulates dendritic growth and will also provide critical insight into the molecular underpinnings of autism and other neurological diseases associated with voltage- gated calcium channel dysfunction.

描述（申请人提供）：树突生长是神经回路发育的关键步骤，在癫痫、自闭症和其他神经系统疾病中受到干扰。电活动通过激活l型电压门控Ca2+通道（LTCs）调节树突乔木的发育和可塑性。本提案的目标是了解LTCs如何调节树突生长和乔木化。为了实现这一目标，我们开发了一种策略，允许我们将突变LTCs引入神经元，并研究这些外源通道如何调节树突乔木。初步研究表明，携带G406R突变的LTCs导致自闭症蒂莫西综合征（TS），其促进树突生长的能力显著受损。我计划描述TS突变LTCs的缺陷，并研究LTCs的其他生物物理和生化特征如何影响通道调节树突状细胞骨架的能力。这些研究将有助于阐明电活动调节树突生长的机制，也将为自闭症和其他与电压门控钙通道功能障碍相关的神经系统疾病的分子基础提供关键的见解。