CONVERGENCE OF BETA 1 AND 2 ADRENERGIC RECEPTOR SIGNALS

描述：（申请人的摘要）至少有九种肾上腺素能 受体（AR）亚型，介导对去甲肾上腺素的反应， 肾上腺素，这是分为三个家庭的相似之处， 结构、药理学和信号传导。 这些亚型在细胞上共存， 对儿茶酚胺的反应通常是由于多种 亚型 首席研究员的研究工作包括继续 研究这些相互作用及其在大脑中的功能意义。 在下一个项目期间，与β AR密切相关的假设 亚型与Gs/腺苷酸环化酶偶联的效率不同 会得到考验 此外，设计实验来评估是否 这些亚型的共存导致会聚信号， 取决于亚型密度和比率的累加、冗余或协同。 实验将在通常不表达AR的细胞系中进行 亚型 诱导型和阻遏型载体将用于控制 大鼠β 1和β 2AR的密度和比例，以及偶联效率 将通过将受体密度与激动剂 刺激反应，范围从GTPgS结合到刺激cAMP， 全细胞 选择性激动剂和拮抗剂将用于比较 单独或组合激活的亚型的偶联效率。 那里 有三个具体目标： 1. 比较两种细胞中大鼠β 1和β 2 AR的偶联效率， 不同的细胞系。 2. 检查Gsa及其亚型表达水平的重要性 每种亚型的偶联效率。 3. 确定由beta1启动的汇聚信号之间的相互作用 和2AR的表达。 这些研究将通过以下方式提供关于信号的具体信息： 儿茶酚胺类神经递质，以及对 在细胞中共存的亚型。 由于已知β AR亚型在 细胞和介导聚合反应，这将有助于理解 各种各样的机制和潜在的治疗方法， 从抑郁症到高血压。

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.