title: Norepinephrine modulates the zonally different hepatocyte proliferation through the regulation of transglutaminase activity.
abstract: A neurotransmitter, norepinephrine (NE), amplifies the mitogenic effect of epidermal growth factor (EGF) in the liver by acting on the alpha(1)-adrenergic receptor coupled with G protein, Galpha(h). However, the molecular mechanism is not well understood. Galpha(h) is known as a transglutaminase 2 (TG2), a cross-linking enzyme implicated in hepatocyte proliferation. We investigated the effect of NE on EGF-induced cell proliferation and TG2 activity using hepatocytes isolated in periportal and perivenous regions of the liver, which differ in proliferative capacity. Periportal hepatocytes (PPH) and perivenous hepatocytes (PVH) were isolated by the digitonin-collagenase perfusion technique. EGF or NE receptor binding was analyzed by Scatchard analysis. Changes in NE-induced DNA synthesis, EGF receptor (EGFR) dimerization and phosphorylation, and TG2 activity were measured. NE enhanced EGF-induced DNA synthesis, EGF-induced EGFR dimerization, and its phosphorylation in PVH but not in PPH. [(3)H]NE binding studies indicated that PVH was found to have a greater affinity and number of receptors than PPH. Furthermore, NE treatment decreased TG2 activity and increased phospholipase C activity in PVH although TG2 level showed no change. These results suggest that NE-induced amplification of EGF-induced DNA synthesis especially in PVH is caused by upregulation of EGFR activation through the switching of function from TG2 to Galpha(h).
authors.affiliation: Department of Radiopharmacy, Tohoku Pharmaceutical Univ., 4-4-1, Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan. y-ohtake@tohoku-pharm.ac.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ohtake
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Akiko
authors.initials: A
authors.lastname: Maruko
authors.forename: Nao
authors.initials: N
authors.lastname: Oh-Ishi
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yamamoto
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Katoh
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Ohkubo
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006868:Hydrolysis; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D054803:Phospholipase C delta / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D055503:Protein Multimerization; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013997:Time Factors; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D018674:Adrenergic Antagonists; C527821:Ghalpha protein, rat; C000717609:Tgm2 protein, rat; D004815:Epidermal Growth Factor; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C483803:Egfr protein, rat; D066246:ErbB Receptors; D054803:Phospholipase C delta; C518026:Plcd1 protein, rat; D019204:GTP-Binding Proteins; D009638:Norepinephrine