当前位置:科学网首页 > 小柯机器人 >详情
研究揭示G蛋白偶联受体35激动剂介导的线粒体重塑和缺血保护作用
作者:小柯机器人 发布时间:2022/8/7 15:15:54

美国哈佛医学院William G. Kaelin, Jr团队揭示G蛋白偶联受体35激动剂介导的线粒体重塑和缺血保护作用。这一研究成果发表在2022年8月4日出版的国际学术期刊《科学》上。

研究人员表示,犬尿酸(KynA)在心、脑、肾和视网膜缺血模型中具有组织保护作用,但其机制尚不清楚。KynA可与多种受体结合,包括芳烃受体、a7尼古丁乙酰胆碱受体(a7nAChR)、多种离子型谷氨酸受体以及孤儿G蛋白偶联受体GPR35。

研究人员表明GPR35的激活对KynA的缺血保护是必要和充分的。当被KynA结合时,GPR35激活了Gi-和G12/13-耦合信号,并转移到线粒体外膜,在那里它显然是间接地与ATP合成酶抑制因子亚单位1(ATPIF1)结合。激活的GPR35以ATPIF1依赖性和百日咳毒素敏感的方式,诱导ATP合成酶二聚化,从而防止缺血时ATP损失。这些发现为开发治疗缺血性疾病的特异性GPR35激动剂提供了理论依据。

附:英文原文

Title: Mitochondrial remodeling and ischemic protection by G protein–coupled receptor 35 agonists

Author: Gregory A. Wyant, Wenyu Yu, IIias P. Doulamis, Rio S. Nomoto, Mossab Y. Saeed, Thomas Duignan, James D McCully, William G. Kaelin, Jr

Issue&Volume: 2022-08-05

Abstract: Kynurenic acid (KynA) is tissue protective in cardiac, cerebral, renal, and retinal ischemia models, but the mechanism is unknown. KynA can bind to multiple receptors, including the aryl hydrocarbon receptor, the a7 nicotinic acetylcholine receptor (a7nAChR), multiple ionotropic glutamate receptors, and the orphan G protein–coupled receptor GPR35. Here, we show that GPR35 activation was necessary and sufficient for ischemic protection by KynA. When bound by KynA, GPR35 activated Gi- and G12/13-coupled signaling and trafficked to the outer mitochondria membrane, where it bound, apparantly indirectly, to ATP synthase inhibitory factor subunit 1 (ATPIF1). Activated GPR35, in an ATPIF1-dependent and pertussis toxin–sensitive manner, induced ATP synthase dimerization, which prevented ATP loss upon ischemia. These findings provide a rationale for the development of specific GPR35 agonists for the treatment of ischemic diseases.

DOI: abm1638

Source: https://www.science.org/doi/10.1126/science.abm1638

 

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037