title: Identification of a receptor-independent activator of G protein signaling (AGS8) in ischemic heart and its interaction with Gbetagamma.
abstract: As part of a broader effort to identify postreceptor signal regulators involved in specific diseases or organ adaptation, we used an expression cloning system in Saccharomyces cerevisiae to screen cDNA libraries from rat ischemic myocardium, human heart, and a prostate leiomyosarcoma for entities that activated G protein signaling in the absence of a G protein coupled receptor. We report the characterization of activator of G protein signaling (AGS) 8 (KIAA1866), isolated from a rat heart model of repetitive transient ischemia. AGS8 mRNA was induced in response to ventricular ischemia but not by tachycardia, hypertrophy, or failure. Hypoxia induced AGS8 mRNA in isolated adult ventricular cardiomyocytes but not in rat aortic smooth muscle cells, endothelial cells, or cardiac fibroblasts, suggesting a myocyte-specific adaptation mechanism involving remodeling of G protein signaling pathways. The bioactivity of AGS8 in the yeast-based assay was independent of guanine nucleotide exchange by Galpha, suggesting an impact on subunit interactions. Subsequent studies indicated that AGS8 interacts directly with Gbetagamma and this occurs in a manner that apparently does not alter the regulation of the effector PLC-beta(2) by Gbetagamma. Mechanistically, AGS8 appears to promote G protein signaling by a previously unrecognized mechanism that involves direct interaction with Gbetagamma.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Sato
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Cismowski
authors.forename: Eiji
authors.initials: E
authors.lastname: Toyota
authors.forename: Alan V
authors.initials: AV
authors.lastname: Smrcka
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Lucchesi
authors.forename: William M
authors.initials: WM
authors.lastname: Chilian
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lanier
mesh_terms: D000818:Animals; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism* / Q000502:physiology; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism* / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D015723:Gene Library; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology
chemical_list: C508124:Fndc1 protein, rat; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D047908:Intracellular Signaling Peptides and Proteins; D019204:GTP-Binding Proteins; D018631:ras Proteins