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; 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（由应用提供）：�-肾上腺素受体（AR）通过激活GS和腺苷酸环化酶（AC）活性刺激cAMP的产生，以诱导平滑的肌肉松弛。毒蕈碱乙酰胆碱受体（MACHR）激活GQ和GI会引起两种原始的收缩：M3受体介导的细胞内Ca2+和M2受体介导的AC活性抑制。 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，主要通过camp依赖性途径诱导松弛。由于这种差异依赖于CAMP，GI耦合的M2受体在胃肠道平滑肌的收缩中起着很大的作用，但在气道平滑肌中不起作用。气道平滑肌过表达AC6表现增强了AR介导的营地形成和放松，但没有增加基本营地水平或对前列腺素EP2受体激活的反应。 AC6过表达的这种选择性作用是由于外源AC6在小窝和脂质筏中与AR的隔室以及从这些微域中排除EP2受体。由于AC的其他同工型与AC6的定位不同，因此该项目将检查气道和回肠平滑肌中的天然AC同工型表达，然后将评估表达脂质筏和非收割的局部AC同工型对这两种组织中收缩张力的生物化学信号传导和调节的影响。中心假设是受体和AC在平滑肌的脂质筏中的定位决定了接收器用于调节收缩张力的信号通路，并且含肌肉的组织之间的这种定位差异。目的是了解受体的细胞区室（主要是集中在bar和machr上）和AC在回肠和气道平滑肌中的AC，并确定这种隔室在调节正常和哮喘气道中平滑肌张力方面的功能重要性。在哮喘或胃肠道疾病中选择性调节平滑肌功能可能会增强AC表达或功能。