Molecular Basis of B1-Adrenergic Receptor Function

B1-肾上腺素受体功能的分子基础

基本信息

批准号：
10618897
负责人：
Xin-Yun Huang
金额：
$ 38.14万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618897
关键词：
Address Adenylate Cyclase Adrenergic Receptor Adrenergic beta-Antagonists Affect American Binding Biochemical Biological Models Biophysics Blood Vessels Cardiac Cardiac Output Catecholamines Cessation of life Chronic Disease Complex Coupling Cryoelectron Microscopy Cyclic AMP Development Disease Electrons Elements Epinephrine Family Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Gases Generations Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Heart Heart Abnormalities Heart Contractilities Heart Diseases Heart Rate Heart failure Heterotrimeric GTP-Binding Proteins Hormones Human Hypertension Mediating Molecular Molecular Conformation Morbidity - disease rate Movement Myocardial Myocardial Infarction Norepinephrine Nucleotides Phosphotransferases Physiological Process Proteins Public Health Receptor Signaling Research Project Grants Role Signal Transduction Specificity Spectrum Analysis Structure System United States beta-arrestin experimental study extracellular global health heart rhythm inhibitor mortality pharmacologic public health relevance receptor receptor binding receptor function response side effect stroke risk

项目摘要

Project Description The long-term objective of this research project is to understand the molecular basis of the activation of heterotrimeric G-proteins by b1-adrenergic receptor. Hypertension (high blood pressure) and heart disease are global health concerns. Hypertension can lead to severe complications and increase the risk of stroke and death. Activation of cardiac b1- adrenergic receptor leads to increased heart rate and contractility, thus boosting cardiac output. Mechanistically, following the stimulation of b1-adrenergic receptor, activated G- protein Gs leads to the stimulation of adenylyl cyclase. In this application, we will focus on the structural basis of activation of Gs-protein by b1-adrenergic receptors. We will use biophysical, cellular and pharmacological approaches to gain a deeper understanding of this activation process. We will investigate the conformational changes of G-proteins during their activation by b1-adrenergic receptors. We will examine the coupling specificity of b1-adrenergic receptors and different families of G-proteins. These studies will advance our understanding of the structure and function of b1-adrenergic receptors, and aid future development of new-generations of specific inhibitors of b1-adrenergic receptors with biased signaling and fewer side effects.

项目描述该研究项目的长期目标是了解 b1-肾上腺素受体激活异三聚体 G 蛋白。高血压（高血压）和心脏病是全球健康问题。高血压可导致严重并发症并增加中风和死亡的风险。心脏b1-的激活肾上腺素能受体导致心率和收缩力增加，从而增强心脏功能输出。从机制上讲，刺激 b1-肾上腺素能受体后，激活 G- 蛋白Gs 会刺激腺苷酸环化酶。在这个应用程序中，我们将重点关注基于b1-肾上腺素受体激活Gs-蛋白的结构基础。我们将使用生物物理、细胞和药理学方法，以获得更深入的了解这个激活过程。我们将研究G蛋白的构象变化在它们被b1-肾上腺素能受体激活的过程中。我们将检查耦合 b1-肾上腺素能受体和不同 G 蛋白家族的特异性。这些研究将增进我们对b1-肾上腺素能受体的结构和功能的理解，并帮助未来开发新一代 b1-肾上腺素能特异性抑制剂具有偏向信号传导和较少副作用的受体。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate.

DOI：
10.1038/s41467-022-28417-2
发表时间：
2022-02-08
期刊：
Nature communications
影响因子：
16.6
作者：
Liu S;Paknejad N;Zhu L;Kihara Y;Ray M;Chun J;Liu W;Hite RK;Huang XY
通讯作者：
Huang XY

Structural basis and mechanism of activation of two different families of G proteins by the same GPCR.

DOI：
10.1038/s41594-021-00679-2
发表时间：
2021-11
期刊：
Nature structural & molecular biology
影响因子：
16.8
作者：
Alegre KO;Paknejad N;Su M;Lou JS;Huang J;Jordan KD;Eng ET;Meyerson JR;Hite RK;Huang XY
通讯作者：
Huang XY