AGING AND G PROTEIN COUPLED RECEPTORS IN HUMAN HEART

衰老与人心脏中的 G 蛋白偶联受体

• 批准号: 6533795
• 负责人: MADAN M KWATRA
• 金额: $ 29.63万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533795
• 关键词: G protein; adenylate cyclase; aging; alpha adrenergic receptor; beta adrenergic receptor; biological signal transduction; enzyme activity; fluorescent dye /probe; gene expression; heart function; human old age (65+); human tissue; immunoprecipitation; isozymes; limbs; muscarinic receptor; phospholipase C; phosphorylation; protein kinase A; protein kinase C; protein structure function; receptor coupling; receptor expression; receptor sensitivity; young adult human (21-34)

Normal functioning of the heart involves several G protein-coupled receptors, including beta-adrenergic, muscarinic, alpha1-adrenergic, endothelin, and angiotensin. Since cardiac performance is profoundly affected by age, it is not surprising that age-related decreases in the responsiveness of cardiac G protein-coupled receptors have been documented. The molecular bases of these decreases, however, remain unknown. Over the past decade, a considerable amount of molecular information on signaling through G protein-coupled receptors has been amassed. Specifically, receptor phosphorylation has emerged as a major factor in GPCR signaling. Extensive studies with beta-adrenergic and muscarinic receptors indicate that these receptors undergo phosphorylation by specific kinases, and this event disrupts receptor/G protein coupling. Catalyzed by receptor-specific kinases (G protein receptor kinase [GRK] isozymes) and second messenger-activated kinases (protein kinase A [PKA] and protein kinase C [PKC] isozymes), receptor phosphorylation appears to be the underlying mechanism for both homologous (agonist-dependent) and heterologous (agonist-independent) desensitization. The proposed studies will delineate the mechanism by which aging produces a decrease in the responsiveness of cardiac G protein-coupled receptors. These studies will be performed on atrial appendages obtained from relatively young (less than or equal to 55 years) and old (greater than or equal to 70 years) patients during cardiac surgery. Our strategy is to first identify the molecular species affected by age and to then determine the underlying mechanism. The first specific aim will test the hypothesis that aging changes the expression of the three main components (receptors/G proteins/effector enzymes) involved in signal transduction through cardiac G protein- coupled receptors. The second specific aim will test the hypothesis that aging diminishes receptor/G protein coupling; here we will examine agonist-stimulated incorporation of 32P-labeled photoaffinity probe azidoanilido-GTP into receptor-associated Galpha-subunits. This approach has not previously been used to assess receptor/G protein coupling in aged heart. The third specific aim will test the hypothesis that aging causes an increase in the activity of protein kinases known to phosphorylate G protein-coupled receptors. The PI's extensive experience in the biochemistry of G protein-coupled receptors and the availability of various reagents in the PI's laboratory (GRK isozymes/G proteins/antibodies) place the PI in a unique position to successfully complete these studies.

心脏的正常功能涉及几个G蛋白偶联

项目成果

Increased expression of Gi-coupled muscarinic acetylcholine receptor and Gi in atrium of elderly diabetic subjects.

老年糖尿病受试者心房中 Gi 偶联毒蕈碱乙酰胆碱受体和 Gi 的表达增加。

• DOI: 10.2337/diabetes.53.9.2392
• 发表时间: 2004
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Richardson,MarkD;Kilts,JasonD;Kwatra,MadanM
• 通讯作者: Kwatra,MadanM

G alpha(q)-coupled receptors in human atrium function through protein kinase C epsilon and delta.

人心房中的 G α(q) 偶联受体通过蛋白激酶 C epsilon 和 delta 发挥作用。

• DOI: 10.1016/j.yjmcc.2004.11.011
• 发表时间: 2005
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Kilts,JasonD;Grocott,HilaryP;Kwatra,MadanM
• 通讯作者: Kwatra,MadanM

Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors.

年龄增加心脏 Galpha(i2) 表达，导致与 G 蛋白偶联受体的偶联增强。

• DOI: 10.1074/jbc.m203640200
• 发表时间: 2002
• 期刊: The Journal of biological chemistry
• 作者: Kilts,JasonD;Akazawa,Toshimasa;Richardson,MarkD;Kwatra,MadanM
• 通讯作者: Kwatra,MadanM

Age increases expression and receptor-mediated activation of G alpha i in human atria.

年龄增加了人类心房中 G α i 的表达和受体介导的激活。

• DOI: 10.1097/00005344-200311000-00013
• 发表时间: 2003
• 期刊: Journal of cardiovascular pharmacology
• 影响因子: 3
• 作者: Kilts,JasonD;Akazawa,Toshimasa;El-Moalem,HabibE;Mathew,JosephP;Newman,MarkF;Kwatra,MadanM
• 通讯作者: Kwatra,MadanM