MOLECULAR CHARACTERIZATION OF H2 RECEPTOR DUAL SIGNALING

H2 受体双信号传导的分子表征

• 批准号: 2147043
• 负责人: JOHN DELVALLE
• 金额: $ 27.54万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2147043
• 关键词: G protein; biological signal transduction; calcium flux; chimeric proteins; cyclic AMP; gastric mucosa; histamine receptor; protein structure function; receptor coupling; synthetic peptide; tissue /cell culture

DESCRIPTION (adapted from investigator's abstract and/or aims): This is a resubmission of an application to study the molecular mechanisms and biological significance of histamine H2 receptor coupling to both cAMP and calcium signaling pathways. Coupling of the H2 receptor to the cAMP pathway is well established; however, histamine H2-receptor associated elevation of intracellular calcium is more recent, having been first observed in rabbit parietal cells in 1986. This observation has now been confirmed in several species including dog and similar data published for HL60 cells.In the parietal cell, numerous studies have demonstrated a clear association between the cAMP pathway and increased HCl secretion; however, the physiological relevance of histamine coupling to the calcium signaling pathway in parietal cells has not been established. Following the recent cloning of the H2 receptor in 1991, the applicant in collaboration with Dr. Yamada and colleagues demonstrated that stable transfection of the H2 receptor into HEPA cells resulted in H2 receptor coupling to adenyl cyclase/cAMP and phospholipase C/calcium/inositol triphosphate (IP3) signaling pathways. The specific aims of this proposal are to continue this line of investigation as follows: 1) To characterize the structural components of the H2 receptor that are linked to the two pathways using chimeric H2 receptors in concert with receptor based synthetic peptides; 2) To characterize the G-proteins involved in dual signaling pathways in both primary and transformed cells; 3) On the basis of knowledge gained from the first two specific aims, to utilize H2 receptor/G-protein-targeted oligopeptides, antisera and antisense probes to determine the relative importance of the dual signaling mechanism in parietal cell secretory activity. Since H2 receptor activation also modulates a number of biologically diverse responses in different cell types, an understanding of its function is expected to have broad biological significance.

描述（改编自研究者的摘要和/或目标）：这是 重新提交研究分子机制的申请 组胺 H2 受体与 cAMP 偶联的生物学意义 和钙信号通路。 H2 受体与 cAMP 的偶联 途径已经建立；然而，组胺 H2 受体相关 细胞内钙的升高是最近才出现的， 1986 年在兔子壁细胞中观察到这一现象。这一观察现在已被证实 已在包括狗在内的多个物种和类似数据中得到证实 针对 HL60 细胞发表。在壁细胞中，大量研究表明 证明 cAMP 通路与增加之间存在明显关联 HCl 分泌；然而，组胺的生理相关性 与壁细胞钙信号通路的耦合尚未被证实 已确立的。 继 1991 年最近克隆 H2 受体之后，申请人 与山田博士及其同事合作证明了稳定的 将 H2 受体转染到 HEPA 细胞中产生 H2 受体 与腺苷酸环化酶/cAMP 和磷脂酶 C/钙/肌醇偶联 三磷酸 (IP3) 信号通路。 本次活动的具体目标 建议继续进行以下调查： 1) 表征 H2 受体的结构成分 使用嵌合 H2 受体与两条通路相联系 基于受体的合成肽； 2) 表征G蛋白 参与原代和转化的双重信号通路 细胞； 3）在前两个具体知识的基础上 目标是利用H2受体/G蛋白靶向寡肽、抗血清 和反义探针以确定双重的相对重要性 壁细胞分泌活动中的信号传导机制。 自 H2 受体激活还调节许多生物多样性 不同细胞类型的反应，了解其功能是 预计具有广泛的生物学意义。