Role of TRPV cation channels in mast cells

TRPV 阳离子通道在肥大细胞中的作用

• 批准号: 6757457
• 负责人: HELEN C TURNER
• 金额: $ 32.3万
• 依托单位: QUEEN'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757457
• 关键词: binding proteins; biological signal transduction; calcium channel; cations; electrophysiology; genetic transcription; mast cell; phenotype; phosphorylation; protein kinase A; protein structure function; site directed mutagenesis; skin; temperature; voltage /patch clamp

DESCRIPTION (provided by applicant): Mast cells are pluripotent effector cells that reside in tissue. They respond to diverse stimuli by releasing potent biological mediators into the surrounding tissue. These mediators include extracellular proteases, histamine and serotonin, as well numerous cytokines, chemokines, and growth factors. Immunologically, mast cells play a crucial role in the generation and maintenance of inflammation, in response to antigenic challenge. In addition to responses to immunological stimulation, mast cells also respond to polybasic secretagogues and physical stimuli. Through responsiveness to physical stimuli (thermal, osmotic and mechanical inputs), mast cells contribute to both tissue homeostasis, and the wounding process that follows noxious insults. Each mechanism for mast cell activation relies on calcium influx through specific plasma membrane cation channels. Here, we report that calcium-permeant cation channels of the TRPV family are expressed in mast cells. TRPV ion channels are a newly recognized family of sensors, which receive, and react to, physical environmental cues, including thermal, osmotic and mechanical stimuli. The central premise of the current proposal is that TRPV channels transduce physiological, and pathophysiological, signals that are functionally coupled to calcium signaling and mediator release in mast cells. We propose to study the regulation, and function, of TRPV cation channels in the mast cell context. Our first Specific Aim tests the hypothesis that expression of TRPV2 confers a specific, thermally-evoked, cation conductance upon mast cells. In the second Specific Aim, we will explore a novel regulatory mechanism for TRPV2. Our preliminary data show that TRPV2 is a target for phosphorylation by protein kinase A in mast cells, and that this interaction is mediated by a novel adapter protein, PAP7. PAP7 specifically bridges TRPV2 and PKA. We will explore the functional consequences and upstream regulatory mechanisms for phosphorylation of TRPV2 by PKA, and the contribution of PAP7. In Specific Aim 3, we will examine the representation and functionality of TRPV channels in dermal mast cells, exploring the hypothesis that TRPVs couple mast cell responses to environmental stimuli in the skin.

描述（由申请人提供）：肥大细胞是存在于组织中的多能效应细胞。它们通过向周围组织释放有效的生物介质来对不同的刺激做出反应。这些介质包括细胞外蛋白酶、组胺和5-羟色胺，以及许多细胞因子、趋化因子和生长因子。在免疫学上，肥大细胞响应抗原攻击，在炎症的产生和维持中起关键作用。除了对免疫刺激的反应外，肥大细胞还对多元促分泌素和物理刺激有反应。 通过对物理刺激（热、渗透和机械输入）的反应，肥大细胞有助于组织稳态和有害损伤后的创伤过程。肥大细胞活化的每种机制都依赖于通过特定质膜阳离子通道的钙内流。在这里，我们报告说，钙渗透阳离子通道的TRPV家族在肥大细胞中表达。TRPV离子通道是近年来发现的一类重要的感受器，它能接收外界的热、渗透压和机械刺激，并对外界的物理环境信号作出反应。目前的建议的中心前提是，TRPV通道的生理和病理生理信号，功能耦合到肥大细胞中的钙信号和介质释放。 我们建议在肥大细胞背景下研究TRPV阳离子通道的调节和功能。我们的第一个特定目标测试了TRPV 2的表达赋予肥大细胞特定的、热诱发的阳离子电导的假设。在第二个具体目标中，我们将探索TRPV 2的新调控机制。我们的初步数据表明，TRPV 2是肥大细胞中蛋白激酶A磷酸化的靶点，这种相互作用是由一种新的衔接蛋白PAP 7介导的。PAP 7特异性桥接TRPV 2和PKA。我们将探讨PKA磷酸化TRPV 2的功能后果和上游调控机制，以及PAP 7的贡献。在具体目标3中，我们将研究TRPV通道在真皮肥大细胞中的代表性和功能，探索TRPV将肥大细胞反应与皮肤中的环境刺激偶联的假设。