RGS3s: an activity dependent regulator of G-proteins

RGS3：G 蛋白的活性依赖性调节剂

• 批准号: 7116450
• 负责人: TARA B SWEET
• 金额: $ 3.78万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116450
• 关键词: G protein; RNA interference; afferent nerve; antiserum; calcium channel; calcium flux; chick embryo; chimeric proteins; electrophysiology; gene mutation; guanosinetriphosphatase activating protein; neural plasticity; neuroregulation; predoctoral investigator; protein isoforms; protein structure function; recombinant proteins; site directed mutagenesis; voltage gated channel

DESCRIPTION (provided by applicant): Acute pain alerts an organism to danger and is crucial to its survival. In contrast, chronic pain arising from pathological functioning of sensory pathways is often debilitating to those afflicted. Voltage-gated calcium channels (VGCCs) are central to both short- and long- term pain mechanisms; they provide a source of calcium influx that alters sensory neuron excitability, exocytosis and gene transcription. G proteins (which inhibit sensory neuron calcium channels) and RGS proteins (which terminate G protein inhibition) together provide dynamic regulation of calcium influx through VGCCs. Such regulation is essential to sensory neuron function and plasticity. My work will focus specifically on the mechanisms and physiological importance of RGS3 in sensory neurons. Preliminary data demonstrates that RGS3 activity is stimulated directly by calcium influx through VGCCs, providing an activity-dependent mechanism to terminate G protein signaling and sustain calcium influx in the active cells. I will use site directed mutagenesis to identify domains in RGS3 important for its calcium-dependent action (Aim 1) and electrophysiological recording to explore calcium-dependent RGS3 activation in native cells under normal physiological conditions (Aim 2). Such information may, in the long term, lead to new strategies to treat chronic pain.

描述（由申请人提供）：急性疼痛提醒生物体注意危险，对其生存至关重要。相反，由感觉通路的病理功能引起的慢性疼痛常常使患者衰弱。电压门控钙通道（VGCC）对于短期和长期疼痛机制都至关重要；它们提供钙流入的来源，改变感觉神经元的兴奋性、胞吐作用和基因转录。 G 蛋白（抑制感觉神经元钙通道）和 RGS 蛋白（终止 G 蛋白抑制）共同提供通过 VGCC 的钙流入的动态调节。这种调节对于感觉神经元功能和可塑性至关重要。我的工作将特别关注 RGS3 在感觉神经元中的机制和生理重要性。初步数据表明，通过 VGCC 的钙流入直接刺激 RGS3 活性，提供了一种活性依赖性机制来终止 G 蛋白信号传导并维持活性细胞中的钙流入。我将使用定点诱变来识别 RGS3 中对其钙依赖性作用至关重要的结构域（目标 1），并使用电生理记录来探索正常生理条件下天然细胞中钙依赖性 RGS3 的激活（目标 2）。从长远来看，这些信息可能会带来治疗慢性疼痛的新策略。