Specific involvement of G αi2 with epidermal growth factor receptor signaling in rat hepatocytes, and the inhibitory effect of chronic ethanol

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We have previously shown that chronic alcohol consumption inhibits liver regeneration by impairing epidermal growth factor receptor (EGFR)-operated phospholipase C- γ1 (PLC- γ1) activation and the resultant rise in intracellular [Ca 2+] i. In hepatocytes, activation of PLC- γ1 by EGFR requires involvement of a pertussis toxin-sensitive inhibitory guanine nucleotide-binding regulatory protein (G αi) as an intermediate. In the present study, we first identified the G αi protein isoform associated with the activated EGFR, and then examined whether the toxic effect of alcohol on EGFR signaling and liver cell proliferation was exerted on this association. In cultured hepatocytes from control rats, EGF rapidly induced association between EGFR and G αi2 but not other G αi isoforms. In hepatocytes from rats fed alcohol for 16 weeks, EGF failed to stimulate this association of G αi2 with the EGFR. The impairment of EGFR-G αi2 complex formation caused by alcohol was associated with a decreased level of G αi2 in the plasma membrane fraction (∼50% control). Pertussis toxin, an inhibitor of G αi function, produced an analogous disruption of the association between G αi2 and the EGFR, as well as inhibiting EGF-induced DNA synthesis. It is concluded that, in hepatocytes, G αi2 is specific among G αi isoforms in coupling activation of the EGFR to other signaling pathways that control cell proliferation. Impaired coupling of G αi2 of EGFR could contribute to the mechanism by which chronic alcohol exposure inhibits liver regeneration.