An obligatory requirement for the heterotrimeric G protein [G.sub.i3] in the antiautophagic action of insulin in the liver

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