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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：
7750516
负责人：
RENNOLDS S OSTROM
金额：
$ 33.76万
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 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750516
关键词：
Address Adenylate Cyclase Adrenergic Receptor Agonist Animals Asthma Biochemical Calcium Caveolae Cell membrane Collaborations Cyclic AMP Data Dependence Enzymes Exclusion Extrinsic asthma G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gastrointestinal Diseases Gene Transfer Goals Hormones Intracellular Second Messenger Isoproterenol 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 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 overexpression programs prostaglandin EP2 receptor receptor receptor coupling respiratory smooth muscle response treatment strategy

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-肾上腺素能受体（BAR）通过激活Gs和腺苷酸环化酶（AC）刺激cAMP产生活性以诱导平滑肌松弛。毒蕈碱型乙酰胆碱受体（mAChR）激活Gq和Gq M3受体介导的细胞内Ca 2+和M2+的升高受体介导的AC活性抑制。（JAR通过两种途径介导气道平滑肌松弛 cAMP依赖性和非依赖性机制，但在胃肠道平滑肌BAR诱导主要通过cAMP依赖性途径舒张。由于对cAMP的依赖性不同， G1偶联M2受体在胃肠平滑肌收缩中起重要作用，但在气道收缩中不起作用。平滑肌过表达AC 6的气道平滑肌显示增强BAR介导的cAMP 形成和舒张，但不增加基础cAMP水平或对前列腺素活化的反应 EP 2受体。AC 6过表达的这种选择性作用似乎是由于细胞膜的区室化。在小窝和脂筏中具有BAR的外源性AC 6以及从这些中排除EP 2受体微域由于AC的其他亚型定位不同于AC 6，因此本项目将研究AC的其他亚型。气道和回肠平滑肌中的天然AC同种型表达然后将评估表达脂筏和非脂筏定位AC亚型对生化信号传导和收缩张力调节的影响这两个组织。中心假设是，受体和AC的脂筏的定位，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之间不同。我们的目标是了解细胞受体的区室化（主要集中在BAR和mAChR上，但不完全集中在BAR和mAChR上）和AC在回肠和气道平滑肌，并确定这种区室化的功能重要性，调节正常和哮喘气道的平滑肌张力。可以提高AC 在哮喘或胃肠道疾病中选择性调节平滑肌功能的表达或功能。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The guinea pig ileum lacks the direct, high-potency, M(2)-muscarinic, contractile mechanism characteristic of the mouse ileum.

DOI：
10.1007/s00210-009-0434-8
发表时间：
2009-10
期刊：
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
影响因子：
3.6
作者：
Griffin, Michael T.;Matsui, Minoru;Ostrom, Rennolds S.;Ehlert, Frederick J.
通讯作者：
Ehlert, Frederick J.

Fibroblast-specific expression of AC6 enhances beta-adrenergic and prostacyclin signaling and blunts bleomycin-induced pulmonary fibrosis.

AC6 成纤维细胞特异性表达可增强 β-肾上腺素能和前列环素信号传导，并减弱博来霉素诱导的肺纤维化。

DOI：
10.1152/ajplung.00429.2009
发表时间：
2010
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
Liu,Xiaoqiu;Li,Fengying;Sun,ShuQiang;Thangavel,Muthusamy;Kaminsky,Joseph;Balazs,Louisa;Ostrom,RennoldsS
通讯作者：
Ostrom,RennoldsS

Non-raft adenylyl cyclase 2 defines a cAMP signaling compartment that selectively regulates IL-6 expression in airway smooth muscle cells: differential regulation of gene expression by AC isoforms.