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