OGR1 is a proton-sensing GPCR in airway smooth muscle

OGR1 是气道平滑肌中的质子感应 GPCR

• 批准号: 8095866
• 负责人: RAYMOND B. PENN
• 金额: $ 25.13万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095866
• 关键词: Acidosis; Acids; Acute; Afferent Neurons; Agonist; Air; Air Pollution; Airway Resistance; Asthma; Biochemistry; Biological Assay; Biology; Bronchoconstriction; Buffers; Cells; Chronic Obstructive Airway Disease; Complex; Contracts; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Event; Exploratory/Developmental Grant; Family; Fogs; Functional disorder; G-Protein-Coupled Receptors; GPR68 gene; Gastroesophageal reflux disease; Goals; Growth; Heterotrimeric GTP-Binding Proteins; Histidine; Human; Indium; Investigation; Lung; MAP Kinase Gene; Mediating; Mediator of activation protein; Modeling; Molecular Biology Techniques; Mus; Muscle Contraction; Muscle function; Obstructive Lung Diseases; Orphan; Pathway interactions; Physiological; Play; Preparation; Protons; Receptor Activation; Recording of previous events; Reflex action; Reflux; Regulation; Research Project Grants; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Solid; Source; Stomach; System; Testing; Tissues; Torture; Work; airway inflammation; airway remodeling; autocrine; base; body system; cell type; clinically relevant; design; extracellular; human GPR68 protein; member; neuromechanism; novel; paracrine; receptor; relating to nervous system; release of sequestered calcium ion into cytoplasm; respiratory smooth muscle; response; second messenger

DESCRIPTION (provided by applicant): Numerous studies suggest alterations in airway pH contribute to the pathophysiology of obstructive airway diseases. Airway acidification can be caused by exogenous as well as endogenous sources including airway inflammation. Neural mechanisms have been shown capable of mediating acidosis-induced bronchoconstriction, but whether reduced pH in the airway microenvironment has direct effects on airway smooth muscle (ASM) is unknown. We have discovered that ASM expresses OGR1, a member of a unique subfamily of G protein-coupled receptors (GPCRs) proposed to be "proton-sensing." Preliminary data suggest OGR1 is expressed in ASM and, in response to reductions in extracellular pH, signals in a manner consistent with pro-contractile Gq-coupled GPCRs. Moreover, tracheal rings are observed to contract ex vivo with modest step decreases in buffer pH that parallel the activation profile of OGR1. Because of the complex issues inherent in analysis of the effect of acidosis/pH in integrative systems, we propose to first undertake a careful, restricted analysis of OGR1 signaling and function in human ASM cells, to establish the relevance of ASM OGR1. Aim 1 will use pharmacological and molecular biology techniques to delineate the signaling events and their requirement for OGR1 in acid-induced signaling and contraction in ASM. Aim 2 will establish activation of OGR1 in ASM involves direct activation of the receptor by protons, while attempting to exclude any role for acid-activated autocrine or paracrine agents. If successful, these studies will identify a novel signaling pathway in ASM that could play a prominent role in the pathobiology of numerous airways diseases, and provide a solid basis for subsequent integrative studies examining the capacity and relevance of pH regulation of OGR1 in ASM and airway function. PUBLIC HEALTH RELEVANCE: Numerous studies suggest that acidification (reduced pH) of the airway, caused by either environmental sources (air pollution) or from within the lung (aspiration of stomach acid, or via airway inflammation) can cause airway smooth muscle to contract and thereby cause or contribute to diseases such as asthma or chronic obstructive pulmonary disease. We have discovered that airway smooth muscle cells express the receptor OGR1 which has recently been proposed to be activated by acidification/reduced pH. Thus OGR1 represents a novel means by which airway smooth muscle might contract when exposed to environmental or endogenous sources of acid. We propose a comprehensive analysis to clarify the ability of OGR1 to signal and function in human airway smooth muscle cells. Successful completion of these studies will identify a novel mechanism of airway smooth muscle contraction and a new target for therapies for obstructive lung diseases.

描述（由申请人提供）：大量研究表明气道pH值的改变有助于阻塞性气道疾病的病理生理学。气道酸化可由外源性和内源性来源引起，包括气道炎症。神经机制已被证明能够介导酸中毒诱导的支气管收缩，但气道微环境中pH值降低是否对气道平滑肌（ASM）有直接影响尚不清楚。我们发现ASM表达OGR 1，它是G蛋白偶联受体（GPCR）中一个独特的亚家族成员，被认为是“质子敏感”的。“初步数据表明，OGR 1在ASM中表达，并且响应于细胞外pH值的降低，以与促收缩Gq偶联的GPCR一致的方式发出信号。此外，观察到气管环离体收缩，缓冲液pH值适度逐步降低，这与OGR 1的激活曲线平行。由于酸中毒/pH在综合系统中的影响分析固有的复杂问题，我们建议首先对人ASM细胞中的OGR 1信号传导和功能进行仔细的、限制性的分析，以确定ASM OGR 1的相关性。目的1将利用药理学和分子生物学技术来阐明平滑肌酸诱导的信号转导和收缩中的信号事件及其对OGR 1的需求。目的2将建立ASM中OGR 1的激活涉及质子直接激活受体，同时试图排除酸激活的自分泌或旁分泌剂的任何作用。如果成功，这些研究将确定一种新的信号通路在ASM中，可以发挥突出的作用，在许多气道疾病的病理生物学，并提供了坚实的基础，为后续的综合研究检查的能力和相关性的pH调节的OGR 1在ASM和气道功能。 公共卫生相关性：许多研究表明，由环境来源（空气污染）或肺内（胃酸吸入或通过气道炎症）引起的气道酸化（pH值降低）可导致气道平滑肌收缩，从而导致或促成哮喘或慢性阻塞性肺病等疾病。我们已经发现，气道平滑肌细胞表达受体OGR 1，最近被提议通过酸化/降低pH来激活。因此，OGR 1代表了一种新的手段，当暴露于环境或内源性酸源时，气道平滑肌可能会收缩。我们提出了一个全面的分析，以澄清OGR 1的信号和功能在人气道平滑肌细胞的能力。这些研究的成功完成将确定气道平滑肌收缩的新机制和阻塞性肺疾病治疗的新靶点。