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␣ i class genes, G␣i2 and G␣i3, demonstrate shared as well as genespecific functions. The presence of a single active allele of G␣i3 is sufficient for embryonic development, whereas at least one allele of G␣ i2 is required for extrauterine life. Mice lacking both G␣i2 and G␣ 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␣ i isoform-specific functions in G␣i2-and G␣i3-deficient mice. The subcellular localization of G␣i3 in isolated mouse hepatocytes depends on the cellular metabolic status. G␣ 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␣ i3 are deficient in the inhibitory action of insulin. These data indicate that G␣ i3 is crucial for the antiautophagic action of insulin and suggest an as-yet-unrecognized function for G␣ i3 on autophagosomal membranes.anticatabolic actions ͉ autophagy ͉ mouse knockout ͉ pertussis toxin-sensitive G proteins

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