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PNAS 103 (3): 797-802

Copyright © 2006 by the National Academy of Sciences.


Identification of a receptor-independent activator of G protein signaling (AGS8) in ischemic heart and its interaction with Gbeta{gamma}

Motohiko Sato *, Mary J. Cismowski {dagger}, Eiji Toyota {ddagger}, Alan V. Smrcka §, Pamela A. Lucchesi *, William M. Chilian {ddagger}, and Stephen M. Lanier *, ¶

Departments of *Pharmacology and Experimental Therapeutics and {ddagger}Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112; {dagger}Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272; and §Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642

Edited by Lutz Birnbaumer, National Institutes of Health, Research Triangle Park, NC, and approved November 18, 2005

Received for publication August 26, 2005.

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 G{alpha}, suggesting an impact on subunit interactions. Subsequent studies indicated that AGS8 interacts directly with Gbeta{gamma} and this occurs in a manner that apparently does not alter the regulation of the effector PLC-beta2 by Gbeta{gamma}. Mechanistically, AGS8 appears to promote G protein signaling by a previously unrecognized mechanism that involves direct interaction with Gbeta{gamma}.

Key Words: accessory protein • signal adaptation • hypoxia

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviation: AGS, activator of G protein signaling.

Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. DQ256268 [GenBank] ).

|| Immunoblotting of nondetergent lysates from AGS8-transfected COS cells with AGS8-specific antibody indicated marked enrichment of AGS8 in the pellet fraction obtained by centrifugation at 100,000 x g. AGS8-C and full-length AGS8 generally elicit a small but consistent increase in inositol phosphate production, suggesting that AGS8 is interacting with endogenous G proteins to increase Gbeta{gamma}-mediated signaling. However, the magnitude of this effect depends on the levels of AGS8 expressed, which is sensitive to the number of plasmids used in the cotransfection experiments.

To whom correspondence should be addressed. E-mail: slanie{at}

© 2006 by The National Academy of Sciences of the USA

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