Beta Andrenergic Receptor Structure and Desensitization

β 肾上腺素能受体结构和脱敏

• 批准号: 7737553
• 负责人: RICHARD B CLARK
• 金额: $ 42.41万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737553
• 关键词: Acute; Address; Adrenal Glands; Adrenergic Agonists; Adrenergic Receptor; Agonist; Antibodies; Area; Arrestins; Asthma; Attention; Binding; Biochemical; Biological Assay; Biological Models; Blood Vessels; Bronchodilation; Bronchodilator Agents; Cancer Center; Cell Line; Cell model; Cell physiology; Cells; Chemistry; Chronic; Chronic Obstructive Airway Disease; Clinical; Collaborations; Complex; Computational Biology; Congestive Heart Failure; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Down-Regulation; Effectiveness; Epinephrine; Equilibrium; Event; Excision; Feedback; Fluorescence Resonance Energy Transfer; G protein coupled receptor kinase; G-Protein-Coupled Receptors; GRK1 gene; GRK5 gene; Goals; Homeostasis; Hormones; Human; Hydrolysis; Incidence; Inflammation; Inhibitory Concentration 50; Intervention; Investigation; Kinetics; Knowledge; Libraries; Link; Lung; Maintenance; Manuscripts; Mediating; Mediation; Medicine; Membrane; Methodology; Modeling; Molecular; Mutagenesis; Myocardial Contraction; N Domain; Nature; Nerve Endings; Neurotransmitters; Norepinephrine; Pathway interactions; Peptide Library; Peptides; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Protein Dephosphorylation; Receptor Activation; Receptor Signaling; Regulation; Relative (related person); Relaxation; Rhodopsin; Role; Second Messenger Systems; Signal Transduction; Simulate; Site; Smooth Muscle; Smooth Muscle Myocytes; Steroids; Stimulus; Structure; Sympathetic Nervous System; System; Systems Biology; Testing; Time; United States; Uterine Contraction; Work; base; college; desensitization; design; fighting; gene therapy; human GRK5 protein; inhibitor/antagonist; kinase inhibitor; mimetics; models and simulation; mutant; novel; overexpression; peptidomimetics; phosphoric diester hydrolase; premature; receptor; receptor function; reconstitution; respiratory smooth muscle; response; second messenger

The 132-adrenergic receptor (132AR) plays a major role in the "fight-or-flight" response including mediation of bronchodilation. Eliciting bronchodilation with agonists of the 132AR is, along with steroids to treat inflammation, a major treatment of chronic asthma. The effectiveness of the bronchodilators is known to decrease over time (desensitize), and as such the characterization of agonist desensitization of the 132AR has been the focus of a multitude of studies, and the evidence derived from these has made it a paradigm for the study of G protein coupled receptors (GPCRs). However, many questions remain concerning the molecular mechanisms of desensitization, and importantly. how the 132AR signaling complex resensitizes following removal of stimulation. At the systems biology level, there is a need for a dynamic modeling of the complex inhibitory feedback loops involving 132AR phosphorylation by PKA and multiple G protein coupled receptor kinase (GRK) subtypes, and their downstream sequelae such as arrestin binding, internalization, and activation of phosphodiesterase. Since most studies of 132AR desensitization have been performed with cell lines overexpressing the 132AR, there is a need for studies of desensitization in primary human cells expressing endogenous levels of the 132AR. Another aspect that has received little attention has been the development of inhibitors of desensitization. Our group has made significant inroads in ongoing studies of three areas of the 132AR desensitization process; characterization of GPCR activation of GRKs, development of a panel of inhibitors of GRK activity, and systems modeling of desensitization and resensitization, leading to the following specific aims: (1) characterization of 132AR desensitization in both HASM and model cell systems with a focus on quantitative systems modeling of the processes that control loss of both 132AR efficacy and downstream actions of the second messenger cAMP through phosphodiesterase hydrolysis; (2) determination of the mechanism of activation of GRKs by the 132AR receptor and the related GPCR rhodopsin through detailed structure/function studies of evolutionarily important GRK residues; and (3) development of peptide inhibitors that disrupt the GPCRlGRK interaction based on knowledge gained of important GRK and 132AR domains involved in the interaction.

132-肾上腺素能受体（132 AR）在“战或逃”反应中起主要作用 包括支气管扩张的调节。用促肾上腺皮质激素激动剂引起支气管扩张 132 AR与类固醇一起沿着用于治疗炎症，是慢性哮喘的主要治疗方法。 已知支气管扩张剂的有效性随时间降低（脱敏）， 因此，132 AR的激动剂脱敏的表征一直是 许多研究的焦点，从这些研究中得出的证据使它成为一个 G蛋白偶联受体（GPCR）的研究范式。但不少 关于脱敏的分子机制仍然存在问题， 重要的是132 AR信号复合物如何在去除 刺激.在系统生物学水平上，需要对系统生物学进行动态建模。 复杂的抑制性反馈环，涉及PKA和多个132 AR磷酸化 G蛋白偶联受体激酶（GRK）亚型及其下游后遗症 例如抑制蛋白结合、内化和磷酸二酯酶的活化。以来 大多数132 AR脱敏研究都是用细胞系进行的 由于132 AR过表达，因此需要研究原发性肝癌的脱敏作用。 表达内源水平的132 AR的人细胞。另一方面， 脱敏抑制剂的开发很少受到关注。我们 该小组在132 AR三个领域的持续研究中取得了重大进展 脱敏过程;表征GRKs的GPCR活化， GRK活性抑制剂的面板，以及脱敏和 再敏化，导致以下具体目标：（1）表征132 AR HASM和模型细胞系统中的脱敏，重点是定量 控制132 AR功效和 第二信使cAMP通过磷酸二酯酶的下游作用 （2）确定132 AR激活GRKs的机制 受体和相关的GPCR视紫红质通过详细的结构/功能研究， 进化上重要的GRK残基;（3）肽抑制剂的开发 基于对重要GRK的了解， 和132个AR结构域参与相互作用。