Adenylyl cyclases in airway and GI smooth muscle

B-肾上腺素能受体(BAR)通过激活Gs和腺苷环化酶(AC)刺激cAMP的产生 诱导平滑肌松弛的活动。M受体(MAChR)激活两个GQ 和GI引起双管齐下的收缩：M3受体介导的细胞内钙和M2的升高 受体介导的AC活性抑制。(JAR通过以下两种途径介导呼吸道平滑肌的松弛 CAMP依赖和非依赖机制，但在胃肠道平滑肌酒吧诱导 松弛主要通过cAMP依赖的途径。由于这种对营地的不同依赖， GI偶联M2受体在胃肠道平滑肌收缩中起重要作用，但在呼吸道中不起作用 平滑的肌肉。过度表达AC6的气道平滑肌显示BAR介导的cAMP增强 形成和松弛，但不增加基础cAMP水平或对前列腺素激活的反应 EP2受体。AC6过度表达的这种选择性效应是由于 小窝和脂筏中带有BAR的外源性AC6及其EP2受体的排斥 微域。由于AC的其他异构体定位不同于AC6，本项目将研究 天然AC异构体在呼吸道和回肠平滑肌中的表达，然后将评估表达的效果 脂筏和非脂筏定位AC异构体对心肌细胞生化信号和收缩张力调节的影响 这两张纸巾。中心假说是受体和AC在脂筏中的定位。 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中是不同的。我们的目标是了解细胞 受体的区隔(主要但不完全集中在bar和mAChR)和AC‘s in 回肠和呼吸道的平滑肌，并确定这种区隔的功能重要性 调节正常和哮喘呼吸道的平滑肌张力。有可能增强交流 在哮喘或胃肠道疾病中选择性地调节平滑肌功能的表达或功能。

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.