Extracellular signal-regulated kinases (ERK) 1 and 2 as well as ERK-5 were previously suggested to phosphorylate connexin-43 and to contribute to the modulation of gap junctional intercellular communication (GJC. Exposure of rat liver epithelial cells to epidermal growth factor (EGF) or the redox cycling and alkylating agent menadione resulted in phosphorylation of connexin-43 and loss in GJC, both of which were abrogated by pharmacological inhibitors of ERK-1/2 activation, if used in concentrations that selectively abrogate phosphorylation of ERK-1/2 but not of ERK-5. Thus, EGF- or menadione-induced loss of GJC is mediated by ERK-1/2 but not ERK-5 in rat liver epithelial cells. (C) 2007 Elsevier Inc. All rights reserved.