Adenylyl cyclases in airway and GI smooth muscle

气道和胃肠道平滑肌中的腺苷酸环化酶

• 批准号: 7544483
• 负责人: RENNOLDS S OSTROM
• 金额: $ 33.96万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-27 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544483
• 关键词: Address; Adenylate Cyclase; Adrenergic Receptor; Agonist; Animals; Asthma; Biochemical; Calcium; Caveolae; Cell membrane; Collaborations; Cyclic AMP; Data; Dependence; Enzymes; Exclusion; Extrinsic asthma; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gastrointestinal Diseases; Gene Transfer; Goals; Hormones; Intracellular Second Messenger; Isoproterenol; Measures; Mediating; Membrane Microdomains; Molecular; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M2 Receptor; Muscarinic M3 Receptor; Muscle Contraction; Muscle Tonus; Muscle function; Muscle relaxation phase; Neurotransmitters; Pathway interactions; Play; Production; Prostaglandins; Protein Isoforms; Regulation; Relative (related person); Relaxation; Research Personnel; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Testing; Tissues; Trachea; Universities; Work; acetylcholine receptor agonist; asthmatic airway; butaprost; experience; extracellular; gastrointestinal; ileum; in vivo Model; insight; mutant; novel therapeutics; overexpression; programs; prostaglandin EP2 receptor; receptor; receptor coupling; respiratory smooth muscle; response; treatment strategy

B-adrenergic receptors (BAR) stimulate cAMP production via activation of Gs and adenylyl cyclase (AC) activity to induce smooth muscle relaxation. Muscarinic acetylcholine receptors (mAChR) activate both Gq and Gi to cause a two-pronged contraction: M3 receptor-mediated elevation of intracellular Ca2+ and M2 receptor-mediated inhibition of AC activity. (JARmediate relaxation of airway smooth muscle via both cAMP-dependent and -independent mechanisms but in gastrointestinal smooth muscle BAR induce relaxation primarily via cAMP-dependent pathways. As a result of this differing dependence upon cAMP, Gi-coupled M2 receptors play a large role in contraction of gastrointestinal smooth muscle but not in airway smooth muscle. Airway smooth muscle overexpressing AC6 display enhanced BAR-mediated cAMP formation and relaxation but not increased basal cAMP levels or response to activation of prostaglandin EP2 receptors. This selective effect of AC6 overexpression appears due to compartmentation of the exogenous AC6 with BAR in caveolae and lipid rafts and the exclusion of EP2 receptors from these microdomains. Because other isoforms of AC localize differently than AC6, this project will examine the native AC isoform expression in airway and ileal smooth muscle then will assess the effects of expressing lipid raft and non-raft localized AC isoforms on biochemical signaling and regulation of contractile tone in these two tissues. The central hypothesis is that the localization of receptors and AC's in lipid rafts of smooth muscle determines the signaling pathways used by receptors to regulate contractile tone and that this localization differs between smooth muscle-containing tissues. The goal is to understand the cellular compartmentation of receptors (focusing primarily, but not exclusively, on BAR and mAChR) and AC's in ileal and airway smooth muscle and to determine the functional importance of this compartmentation in regulation of smooth muscle tone in both normal and asthmatic airways. It may be possible to enhance AC expression or function to selectively regulate smooth muscle function in asthma or gastrointestinal disease.

B-肾上腺素能受体（BAR）通过激活Gs和腺苷酸环化酶（AC）刺激cAMP产生 活性以诱导平滑肌松弛。毒蕈碱型乙酰胆碱受体（mAChR）激活Gq和Gq M3受体介导的细胞内Ca 2+和M2+的升高 受体介导的AC活性抑制。（JAR通过两种途径介导气道平滑肌松弛 cAMP依赖性和非依赖性机制，但在胃肠道平滑肌BAR诱导 主要通过cAMP依赖性途径舒张。由于对cAMP的依赖性不同， G1偶联M2受体在胃肠平滑肌收缩中起重要作用，但在气道收缩中不起作用。 平滑肌过表达AC 6的气道平滑肌显示增强BAR介导的cAMP 形成和舒张，但不增加基础cAMP水平或对前列腺素活化的反应 EP 2受体。AC 6过表达的这种选择性作用似乎是由于细胞膜的区室化。 在小窝和脂筏中具有BAR的外源性AC 6以及从这些中排除EP 2受体 微域由于AC的其他亚型定位不同于AC 6，因此本项目将研究AC的其他亚型。 气道和回肠平滑肌中的天然AC同种型表达然后将评估表达 脂筏和非脂筏定位AC亚型对生化信号传导和收缩张力调节的影响 这两个组织。中心假设是，受体和AC的脂筏的定位， 平滑肌决定受体用来调节收缩张力的信号通路， 这种定位在含有平滑肌的组织之间不同。我们的目标是了解细胞 受体的区室化（主要集中在BAR和mAChR上，但不限于此）和AC 回肠和气道平滑肌，并确定这种区室化的功能重要性， 调节正常和哮喘气道的平滑肌张力。可以提高AC 在哮喘或胃肠道疾病中选择性调节平滑肌功能的表达或功能。