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: 7033200
• 负责人: RENNOLDS S OSTROM
• 金额: $ 34.43万
• 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/7033200
• 关键词: adenylate cyclase; asthma; beta adrenergic receptor; biological signal transduction; cell surface receptors; cyclic AMP; enzyme activity; gastrointestinal epithelium; guinea pigs; ileum; isoproterenol; laboratory mouse; lipid raft; muscarinic receptor; muscle relaxation; pathologic process; receptor expression; respiratory epithelium; smooth muscle; tissue /cell culture; trachea

DESCRIPTION (provided by applicant): ¿-adrenergic receptors (¿AR) 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. ¿AR mediate relaxation of airway smooth muscle via both cAMP-dependent and -independent mechanisms but in gastrointestinal smooth muscle ¿AR 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 ¿AR-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 ¿AR 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.

描述(由申请人提供)：肾上腺素能受体(AR)通过激活Gs和腺苷环化酶(AC)活性来刺激cAMP的产生，从而诱导平滑肌松弛。M受体(MAChR)同时激活GQ和GI，引起双管齐下的收缩：M3受体介导的细胞内钙升高和M2受体介导的AC活性抑制。AR通过cAMP依赖和非依赖两种机制介导气道平滑肌的松弛，但在胃肠平滑肌中，AR主要通过cAMP依赖的途径诱导松弛。由于对cAMP的这种不同依赖，Gi偶联的M2受体在胃肠平滑肌的收缩中发挥重要作用，而在呼吸道平滑肌中则不起作用。过度表达AC6的气道平滑肌显示增强AR介导的cAMP形成和松弛，但不增加基础cAMP水平或对前列腺素EP2受体激活的反应。AC6过度表达的这种选择性效应是由于外源AC6与AR在小窝和脂筏中的区隔以及EP2受体被排除在这些微域之外。由于AC的其他异构体与AC6的定位不同，本项目将检测天然AC异构体在呼吸道和回肠平滑肌中的表达，然后评估表达脂筏和非RAFT定位的AC异构体对这两个组织中生化信号和收缩张力调节的影响。中心假说是，受体和AC在平滑肌脂筏中的定位决定了受体调节收缩张力的信号通路，而且这种定位在含有平滑肌的组织中是不同的。其目的是了解回肠和气道平滑肌中受体(主要集中于BAR和mAChR)和AC的细胞区隔，并确定这种区隔在调节正常和哮喘呼吸道的平滑肌张力中的功能重要性。在哮喘或胃肠道疾病中，有可能通过增强AC的表达或功能来选择性地调节平滑肌功能。