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PNAS 104 (8): 3003-3008

Copyright © 2007 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / PHARMACOLOGY

An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver

Antje Gohla*, Karinna Klement*, Roland P. Piekorz*, Katja Pexa*, Stephan vom Dahl{dagger},{ddagger}, Karsten Spicher*,§, Vladyslav Dreval*, Dieter Häussinger{dagger}, Lutz Birnbaumer,||, and Bernd Nürnberg*,**

*Institut für Biochemie und Molekularbiologie II and {dagger}Klinik für Gastroenterologie, Hepatologie, und Infektiologie, Klinikum der Heinrich-Heine-Universität, D-40225 Düsseldorf, Germany; §Institut für Pharmakologie, Charité-Universitätsmedizin, D-14195 Berlin, Germany; and Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709

Contributed by Lutz Birnbaumer, December 21, 2006

Received for publication December 7, 2006.

Abstract: Heterotrimeric G proteins of the Gi class have been implicated in signaling pathways regulating growth and metabolism under physiological and pathophysiological conditions. Knockout mice carrying inactivating mutations in both of the widely expressed G{alpha}i class genes, G{alpha}i2 and G{alpha}i3, demonstrate shared as well as gene-specific functions. The presence of a single active allele of G{alpha}i3 is sufficient for embryonic development, whereas at least one allele of G{alpha}i2 is required for extrauterine life. Mice lacking both G{alpha}i2 and G{alpha}i3 are massively growth-retarded and die in utero. We have used biochemical and cell biological methods together with in situ liver perfusion experiments to study G{alpha}i isoform-specific functions in G{alpha}i2- and G{alpha}i3-deficient mice. The subcellular localization of G{alpha}i3 in isolated mouse hepatocytes depends on the cellular metabolic status. G{alpha}i3 localizes to autophagosomes upon starvation-induced autophagy and distributes to the plasma membrane upon insulin stimulation. Analysis of autophagic proteolysis in perfused mouse livers showed that mice lacking G{alpha}i3 are deficient in the inhibitory action of insulin. These data indicate that G{alpha}i3 is crucial for the antiautophagic action of insulin and suggest an as-yet-unrecognized function for G{alpha}i3 on autophagosomal membranes.

Key Words: anticatabolic actions • autophagy • mouse knockout • pertussis toxin-sensitive G proteins

Author contributions: A.G., R.P.P., L.B., and B.N. designed research; K.K., R.P.P., K.P., S.v.D., K.S., and V.D. performed research; S.v.D. and D.H. contributed new reagents/analytic tools; A.G., R.P.P., S.v.D., D.H., L.B., and B.N. analyzed data; and A.G., L.B., and B.N. wrote the paper.

{ddagger}Present address: St. Franziskus-Hospital, Schönsteinstrasse 63, 50825 Köln, Germany.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0611434104/DC1.

||To whom correspondence may be addressed. E-mail: birnbau1{at}niehs.nih.gov

**To whom correspondence may be addressed at: Institut für Biochemie und Molekularbiologie II, Geb. 22.03.03, Klinikum der Heinrich-Heine-Universität, D-40225 Düsseldorf, Germany. E-mail: bernd.nuernberg{at}uni-duesseldorf.de

© 2007 by The National Academy of Sciences of the USA

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