Malik S, deRubio R G, Trembley M, Irannejad R, Wedegaertner P B, Smrcka A V
Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642.
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158.
Mol Biol Cell. 2015 Mar 15;26(6):1188-98. doi: 10.1091/mbc.E14-10-1476. Epub 2015 Jan 21.
We recently identified a novel GPCR-dependent pathway for regulation of cardiac hypertrophy that depends on Golgi phosphatidylinositol 4-phosphate (PI4P) hydrolysis by a specific isoform of phospholipase C (PLC), PLCε, at the nuclear envelope. How stimuli are transmitted from cell surface GPCRs to activation of perinuclear PLCε is not clear. Here we tested the role of G protein βγ subunits. Gβγ inhibition blocked ET-1-stimulated Golgi PI4P depletion in neonatal and adult ventricular myocytes. Blocking Gβγ at the Golgi inhibited ET-1-dependent PI4P depletion and nuclear PKD activation. Translocation of Gβγ to the Golgi stimulated perinuclear Golgi PI4P depletion and nuclear PKD activation. Finally, blocking Gβγ at the Golgi or PM blocked ET-1-dependent cardiomyocyte hypertrophy. These data indicate that Gβγ regulation of the perinuclear Golgi PI4P pathway and a separate pathway at the PM is required for ET-1-stimulated hypertrophy, and the efficacy of Gβγ inhibition in preventing heart failure maybe due in part to its blocking both these pathways.
我们最近发现了一种新的依赖G蛋白偶联受体（GPCR）的心脏肥大调节途径，该途径依赖于磷脂酶C（PLC）的一种特定亚型PLCε在核膜处对高尔基体磷脂酰肌醇4-磷酸（PI4P）的水解作用。目前尚不清楚刺激信号是如何从细胞表面GPCR传递至核周PLCε激活的。在此，我们检测了G蛋白βγ亚基的作用。抑制Gβγ可阻断内皮素-1（ET-1）刺激的新生和成年心室肌细胞中高尔基体PI4P的消耗。在高尔基体处阻断Gβγ可抑制ET-1依赖的PI4P消耗和核蛋白激酶D（PKD）激活。Gβγ向高尔基体的转位刺激了核周高尔基体PI4P的消耗和核PKD激活。最后，在高尔基体或质膜处阻断Gβγ可阻断ET-1依赖的心肌细胞肥大。这些数据表明，ET-1刺激的肥大需要Gβγ对核周高尔基体PI4P途径和质膜处另一条途径的调节，并且Gβγ抑制在预防心力衰竭方面的有效性可能部分归因于其对这两条途径的阻断作用。
