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

基本信息

批准号：
7339021
负责人：
RENNOLDS S OSTROM
金额：
$ 34.17万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
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/7339021
关键词：
Address Adenylate Cyclase Adrenergic Receptor Agonist Animals Asthma Biochemical Calcium Caveolae Cell membrane Collaborations Cyclic AMP Data Dependence Elevation Enzymes Exclusion Extrinsic asthma G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gastrointestinal Diseases Gene Transfer Goals Hormones Intracellular Second Messenger Isoproterenol Localized 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 Protein Overexpression 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 programs prostaglandin EP2 receptor receptor receptor coupling respiratory smooth muscle response

Address Adenylate Cyclase Adrenergic Receptor Agonist Animals Asthma Biochemical Calcium Caveolae Cell membrane Collaborations Cyclic AMP Data Dependence Elevation Enzymes Exclusion Extrinsic asthma G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gastrointestinal Diseases Gene Transfer Goals Hormones Intracellular Second Messenger Isoproterenol Localized 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 Protein Overexpression 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 programs prostaglandin EP2 receptor receptor receptor coupling respiratory smooth muscle response

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项目摘要

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-肾上腺素受体（BAR）通过激活GS和腺苷酸环化酶（AC）刺激cAMP的产生活动以诱导平滑肌肉放松。毒蕈碱乙酰胆碱受体（MACHR）激活两个GQ 和GI引起两种原始的收缩：M3受体介导的细胞内Ca2+和M2升高受体介导的AC活性抑制。（通过两者都放松气道平滑肌的放松依赖营地的和非依赖的机制，但在胃肠道平滑肌条中诱导放松主要通过cAMP依赖的途径。由于这种对训练营的不同依赖， GI耦合的M2受体在胃肠道平滑肌收缩中起着很大的作用，但在气道中不发挥作用平滑肌。气道平滑肌过表达AC6显示增强的棒介导的营地形成和放松，但不能增加基础营地或对前列腺素激活的反应 EP2受体。 AC6过表达的这种选择性效应是由于隔间的外源AC6在小窝和脂质筏中带有杆，并排除EP2受体微域。由于AC的其他同工型与AC6不同，因此该项目将检查在气道和回肠平滑肌中的天然AC同工型表达将评估表达的影响脂质筏和非生殖局部AC同工型在生化信号传导和收缩调节中的调节这两个组织。中心假设是受体和AC在脂质筏中的定位平滑肌确定受体用于调节收缩音的信号通路，并且这种定位在含平滑肌的组织之间有所不同。目标是了解细胞受体的隔室（主要是（但不是仅专注于酒吧和MACHR））和AC在回肠和气道平滑肌，并确定此隔室的功能重要性在正常和哮喘气道中调节平滑肌张力。可以增强交流电表达或功能以选择性调节哮喘或胃肠道疾病中的平滑肌功能。