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Molecular signal transduction of cAMP compartments

cAMP 区室的分子信号转导

基本信息

批准号：
10438686
负责人：
RENNOLDS S OSTROM
金额：
$ 30.04万
依托单位：
CHAPMAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438686
关键词：
A kinase anchoring protein Adenylate Cyclase Adverse effects Asthma Biochemical Biological Models Biotin Buffers Cataloging Cell Differentiation process Cell membrane Cell model Cell physiology Cells Chronic Obstructive Pulmonary Disease Complex Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Diffusion Disease Elements Enzymes Event Fibroblasts Fibrosis Fluorescence Resonance Energy Transfer G-Protein-Coupled Receptors Goals Heart failure Hormone Receptor Human Hypertension Individual Kinetics Label Lead Ligase Lipids Locales Location Measures Membrane Microdomains Methods Molecular Monitor Nature Neurotransmitter Receptor Pharmaceutical Preparations Physiological Play Positioning Attribute Production Protein Isoforms Proteins Proteomics Receptor Signaling Reporting Role Second Messenger Systems Shapes Signal Transduction Signaling Protein Small Interfering RNA Smooth Muscle Myocytes Stroke Study models Techniques Therapeutic Time Vascular Diseases Work base design fluorophore innovation interdisciplinary approach knock-down member mutant novel novel therapeutics phosphoproteomics phosphoric diester hydrolase prevent public health relevance receptor respiratory smooth muscle response scaffold sensor sensor technology tool

项目摘要

A large number of G protein coupled receptors (GPCR) utilize cAMP as their second messenger to alter cell function. In fact, in the same cell several different GPCR can increase cAMP, leading to the question of how the cell interprets the signals from these receptors differently. The concept of cAMP compartmentation, where the second messenger is not generated uniformly throughout the cell, is readily accepted yet poorly understood. The enzymes that synthesize cAMP, adenylyl cyclases (ACs), are not uniformly distributed through the plasma membrane. Furthermore, GPCR can preferentially couple to certain AC isoforms due to colocalization in lipid rafts or non-raft domains. While we have made progress in understanding how specific receptors can couple to different ACs, little progress has been made in defining the compartments of cAMP inside cells and how cellular responses can be modified by different pools of cAMP. Commonly used cell models are de-differentiated and lack highly compartmentized cAMP pools. However, we have defined two clear cAMP signaling compartments in primary human airway smooth muscle (HASM) cells. The goal of this project is to characterize the key regulatory components, PDEs and AKAPs, in these two cAMP compartments and to discover novel protein members of signaling complexes therein. We will use siRNA to knockdown individual PDEs and AKAPs then measure localized cAMP signals via novel fluorescent sensors. We have defined the phosphoproteomic signatures of each cAMP compartment using quantitative phosphoproteomics, so will leverage these signatures to infer roles for individual PDEs or AKAPs following knockdown. State-of-the- art spectroscopic methods will directly assess the diffusion of cAMP in cells. Finally, we will use biotin proximity labeling to identify AC-interacting proteins in both HASM and less well differentiated HEK-293 cells. This project proposes innovative, multidisciplinary approaches to define the components responsible for establishing and maintaining cAMP signaling compartments. Our findings will have broad applicability due to the fundamental nature of cAMP signaling, but will also have direct relevance to asthma and COPD therapy.

大量的G蛋白偶联受体（GPCR）利用cAMP作为第二信使改变细胞

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantitative phosphoproteomic analysis reveals unique cAMP signaling pools emanating from AC2 and AC6 in human airway smooth muscle cells.

DOI：
10.3389/fphys.2023.1149063
发表时间：
2023
期刊：
Frontiers in physiology
影响因子：
4
作者：
通讯作者：

Compartmentalized cAMP signaling in cardiac ventricular myocytes.

DOI：
10.1016/j.cellsig.2021.110172
发表时间：
2022-01
期刊：
Cellular signalling
影响因子：
4.8
作者：
Agarwal SR;Sherpa RT;Moshal KS;Harvey RD
通讯作者：
Harvey RD

A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism.

DOI：
10.1038/mp.2016.104
发表时间：
2017-07
期刊：
Molecular psychiatry
影响因子：
11
作者：
Wang B;Liu Y;Huang L;Chen J;Li JJ;Wang R;Kim E;Chen Y;Justicia C;Sakata K;Chen H;Planas A;Ostrom RS;Li W;Yang G;McDonald MP;Chen R;Heck DH;Liao FF
通讯作者：
Liao FF

Phosphodiesterase 7B regulates prostanoid- but not ß-adrenergic-stimulated cAMP levels in primary human airway smooth muscle cells.

磷酸二酯酶 7B 调节人原代气道平滑肌细胞中前列腺素刺激的 cAMP 水平，但不调节 β-肾上腺素刺激的 cAMP 水平。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
McCuthcheon,DayanitaP;Fariborzi,Mona;Cattani-Cavalieri,Isabella;Nuñez,FranciscoJ;Roosan,MoomR;Ostrom,RennoldsS
通讯作者：
Ostrom,RennoldsS