CONVERGENCE OF BETA 1- & 2-ADRENERGIC RECEPTOR SIGNALS

Beta 1 的收敛性-

• 批准号: 2445733
• 负责人: Kenneth P Minneman
• 金额: $ 19.83万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2445733
• 关键词: G protein; PC12 cells; adenylate cyclase; adrenergic agents; alpha adrenergic receptor; antisense nucleic acid; beta adrenergic receptor; catecholamines; cyclic AMP; gene induction /repression; guanosine triphosphate; inhibitor /antagonist; neuropharmacology; neurotransmitters; polymerase chain reaction; protein isoforms; receptor coupling; receptor expression; transfection; transfection /expression vector; western blottings

DESCRIPTION: (Applicant's abstract) There are at least nine adrenergic receptor (AR) subtypes which mediate responses to norepinephrine and epinephrine, which are grouped into three families with similarities in structure, pharmacology, and signalling. These subtypes coexist on cells, and responses to catecholamines are often due to activation of multiple subtypes. The principal investigator's research efforts involve continuing to examine these interactions and their functional implications in brain. During the next project period, the hypothesis that closely related betaAR subtypes differ in their efficiencies of coupling to Gs/adenylate cyclase will be tested. In addition, experiments are designed to evaluate whether coexistence of these subtypes results in converging signals which can be additive, redundant or synergistic dependent on subtype density and ratio. Experiments will be performed in cell lines that normally express no AR subtypes. Inducible and repressible vectors will be used to control the densities and ratios of rat beta1 and beta2ARs, and efficiency of coupling will be quantified by relating receptor density to the ability of agonists to stimulate responses, ranging from GTPgS binding to stimulation of cAMP in whole cells. Selective agonists and antagonists will be used to compare coupling efficiencies of subtypes activated alone or in combinations. There are three specific aims: 1. Compare the coupling efficiencies of rat beta1 and beta2ARs in two different cell lines. 2. Examine the importance of the expression level of Gsa and its isoforms in the coupling efficiency of each subtype. 3. Determine the interactions between converging signals initiated by beta1 and 2ARs when coexpressed in various densities and ratios. These studies will provide specific information on signalling by catecholamine neurotransmitters, and insights into the implications of coexisting subtypes in cells. Since betaAR subtypes are known to coexist on cells and mediate converging responses, this will be useful in understanding the mechanisms and potential therapeutic approaches for a variety of diseases from depression to hypertension.

描述：(申请人摘要)至少有九种肾上腺素能 受体(AR)亚型介导对去甲肾上腺素和 肾上腺素被分成三个家族，它们在 结构、药理和信号。这些亚型共存于细胞上， 对儿茶酚胺的反应通常是由于激活多个 子类型。首席调查员的研究工作包括继续 来研究这些相互作用及其在大脑中的功能含义。 在下一个项目期间，与BetaAR密切相关的假设 亚型与Gs/腺苷环化酶偶联的效率不同 将会受到考验。此外，还设计了一些实验来评估 这些子类型的共存导致汇聚信号，这可能是 相加、冗余或协同作用取决于亚型密度和比例。 实验将在通常不表达AR的细胞系中进行 子类型。可诱导和可抑制的矢量将用于控制 大鼠β_1和β_2受体的密度、比率和偶联效率 将通过将受体密度与激动剂的能力相关联来量化 刺激反应，从GTPgS结合到刺激cAMP在 整个细胞。选择性激动剂和拮抗剂将用于比较 单独激活或组合激活的亚型的耦合效率。那里 有三个具体目标： 1.比较大鼠Beta1和Beta2AR在两种情况下的偶联效率 不同的细胞系。 2.检测GSA及其异构体表达水平的重要性 各亚型的耦合效率。 3.确定Beta1发起的汇聚信号之间的相互作用 当以不同的密度和比例共表达时，2AR。 这些研究将提供有关通过以下方式发送信号的具体信息 儿茶酚胺类神经递质，以及对 单元格中共存的子类型。由于已知BetaAR子类型共存于 细胞和中介会聚反应，这将有助于理解 多种疾病的发病机制及可能的治疗方法 从抑郁症到高血压的各种疾病。