Specific involvement of G(alphai2) with epidermal growth factor receptor signaling in rat hepatocytes, and the inhibitory effect of chronic ethanol.
We have previously shown that chronic alcohol consumption inhibits liver regeneration by impairing epidermal growth factor receptor (EGFR)-operated phospholipase C-(gamma1) (PLC-(gamma1)) activation and the resultant rise in intracellular [Ca(2+)](i). In hepatocytes, activation of PLC-(gamma1) by EGFR requires involvement of a pertussis toxin-sensitive inhibitory guanine nucleotide-binding regulatory protein (G(alphai)) as an intermediate. In the present study, we first identified the G(alphai) 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(alphai2) but not other G(alphai) isoforms. In hepatocytes from rats fed alcohol for 16 weeks, EGF failed to stimulate this association of G(alphai2) with the EGFR. The impairment of EGFR-G(alphai2) complex formation caused by alcohol was associated with a decreased level of G(alphai2) in the plasma membrane fraction (approximately 50% control). Pertussis toxin, an inhibitor of G(alphai) function, produced an analogous disruption of the association between G(alphai2) and the EGFR, as well as inhibiting EGF-induced DNA synthesis. It is concluded that, in hepatocytes, G(alphai2) is specific among G(alphai) isoforms in coupling activation of the EGFR to other signaling pathways that control cell proliferation. Impaired coupling of G(alphai2) of EGFR could contribute to the mechanism by which chronic alcohol exposure inhibits liver regeneration.
Zhang
B H
BH
Storr Liver Unit, Department of Medicine and Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW 214, Westmead, Australia.
Ho
V
V
Farrell
G C
GC
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004347:Drug Interactions; D066246:ErbB Receptors / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology*; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D037342:Pertussis Toxin; D020033:Protein Isoforms / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D010566:Virulence Factors, Bordetella; D000431:Ethanol; D000244:Adenosine Diphosphate; D037342:Pertussis Toxin; D066246:ErbB Receptors; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498017:Gnai2 protein, rat