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 和腺苷酸环化酶 (AC) 活性刺激 cAMP 产生，从而诱导平滑肌松弛；毒蕈碱乙酰胆碱受体 (mAChR) 激活 Gq 和 Gi，从而引起双管齐下的收缩：M3 受体介导。 ¿细胞内 Ca2+ 和 M2 受体介导的 AC 活性抑制作用升高。 AR 通过 cAMP 依赖性和非依赖性机制介导气道平滑肌的松弛，但在胃肠道平滑肌中 ¿ AR 主要通过 cAMP 依赖性途径诱导松弛，由于对 cAMP 的这种不同依赖性，Gi 偶联 M2 受体在胃肠道平滑肌收缩中发挥重要作用，但在气道平滑肌过度表达 AC6 中却没有作用。 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 ¿小窝和脂筏中的 AR 以及从这些微结构域中排除 EP2 受体，因为 AC 的其他亚型的定位与 AC6 不同，因此该项目将检查气道和回肠平滑肌中的天然 AC 亚型表达，然后评估表达脂筏的影响。和非筏定位的 AC 亚型对这两种组织中的生化信号传导和收缩张力的调节的影响。中心假设是受体和 AC 位于平滑肌的脂筏中。确定受体用于调节收缩张力的信号传导途径，并且这种定位在含有平滑肌的组织之间有所不同。目标是了解回肠中受体（主要但不限于 BAR 和 mAChR）和 AC 的细胞区划。和气道平滑肌，并确定这种区室在调节正常和哮喘气道平滑肌张力中的功能重要性。增强AC表达或功能以选择性调节哮喘或哮喘气道中的平滑肌功能是可能的。胃肠道疾病。