The Role of Calcyon in Synaptic Integration

Calcyon 在突触整合中的作用

• 批准号: 6320696
• 负责人: CLARE M BERGSON
• 金额: $ 25.11万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6320696
• 关键词: autoradiography; biological signal transduction; calcium indicator; calcium ion; cell line; confocal scanning microscopy; dopamine receptor; immunocytochemistry; immunoprecipitation; ion transport; membrane proteins; neural transmission; phosphorylation; protein protein interaction; protein structure function; receptor coupling; synapses; yeast two hybrid system

DESCRIPTION (provided by applicant): Obtaining a precise understanding of the mechanism(s) by which endogenous neuromodulators such as dopamine (DA) regulate glutamergic excitatory transmission could lead to better for patients afflicted with epilepsy, Parkinson's Disease, schizophrenia, and drug addiction. Activation of the D1 dopamine receptor subtype, in particular, modulates glutamate-induced neuronal excitability in frontal cortex, hippocampus and neostriatum. Little is known about molecular mechanism(s) by which D1 receptor signaling modulates excitatory transmission. We recently identified a single transmembrane protein designated Calcyon which interacts with D1 DA receptors and localizes to vesicles in dendritic spines. Via interaction with Calcyon, D1 receptors stimulate release of Ca++ from internal stores (Ca++i) in an activity-dependent manner in heterologous expression system. A similar activity-dependent, D1 receptor agonist stimulated response is detectable by Fura-2 Ca++ imaging of primary cultures of cortical and hippocampal neurons. Our overarching hypothesis is that Calcyon enhances D1 receptor signaling through Gq/11 by serving as a link connecting D1 receptors to IP3 regulated Ca++ stores. We will determine how D1 DA receptor signaling through Gq/11 is primed, and how Calcyon enhances D1 receptor-mediated IP3 signaling. Using Ca++ imaging and peptides to block the D1 receptor:Calcyon interaction, we will determine if Calcyon is required for D1 agonist stimulated Ca++i release in dendritic spines. We propose to identify other GPCRs and accessory proteins that interact with Calcyon by yeast two-hybrid and phage display screens. We will determine how these proteins are involved in regulating release of Ca++ from vesicular stores. The results of this research should provide insight into clinical strategies to selectively boost or dampen D1 receptor mediated neuromodulation of excitatory transmission.

描述（由申请人提供）：对 内源性神经调节剂（例如多巴胺（DA））调节的机制 谷氨酸兴奋性的传播可能会导致患者较好 癫痫，帕金森氏病，精神分裂症和吸毒成瘾。 D1多巴胺受体亚型的激活，特别是调节 谷氨酸诱导的额叶皮质，海马和 新纹状体。关于D1受体的分子机制知之甚少 信号传导调节兴奋性传播。我们最近确定了一个 跨膜蛋白指定的结石与D1 DA受体相互作用 并将其定位于树突状棘中的囊泡。通过与Colcyon的相互作用D1 受体刺激从内部商店（Ca ++ i）中释放Ca ++ 异源表达系统中的活动依赖性方式。类似 活性依赖性D1受体激动剂刺激的反应可通过 fura-2 Ca ++成像皮质和海马神经元的原发性培养物。 我们的总体假设是Colcyon增强了D1受体信号传导 通过将D1受体连接到IP3调节的链接，通过GQ/11通过 Ca ++商店。我们将确定通过GQ/11的D1 DA受体信号传导如何 启动，以及Colcyon如何增强D1受体介导的IP3信号传导。使用Ca ++ 成像和肽阻断D1受体：Cycyon相互作用，我们将 确定D1激动剂刺激Ca ++ I是否需要Colcyon I释放 树突状刺。我们建议识别其他GPCR和配件蛋白 通过酵母两杂交和噬菌体显示屏幕与Colcyon相互作用。我们 将确定这些蛋白如何参与调节Ca ++的释放 来自囊泡商店。这项研究的结果应洞悉 选择性增强或抑制D1受体介导的临床策略 兴奋性传播的神经调节。