Gap junction blockage promotes cadmium-induced apoptosis in BRL 3A rat liver cells.

Gap junctions mediate direct communication between cells. Toxicological cascade triggered by nonessential metals can abrogate cellular signaling mediated by gap junctions. Cadmium (Cd) is a cytotoxic industrial and environmental pollutant. Although Cd is known to induce apoptosis in organs and tissues, the mechanisms that underlie gap junction activity in Cd-induced apoptosis in BRL 3A cells is not established. In this study, we showed that Cd treatment decreased cell index (a measure of cellular electrical impedance) in BRL 3A cells. Mechanistically, we observed that Cd exposure decreased expression of connexin 43 (Cx43), increased expression of p-Cx43 and elevated intracellular free Ca(2+)concentration ([Ca(2+)]i), corresponding to a decrease in gap junctional intercellular communication. Gap junction blockage pretreatment with 18β-glycyrrhizic acid (GA) promoted Cd-induced apoptosis involving changes in expression of Bax, Bcl-2, Caspase-3 and the mitochondrial transmembrane electrical potential (ΔΨm). Additionally, it was observed that GA enhanced ERK and p38 activation during Cd-induced activation of mitogen-activated protein kinases, but had no significant effect on JNK activation. Our results indicated that the apoptosis-related proteins and the ERK and p38 signaling pathways may participate in gap junction blockage promoting Cd-induced apoptosis in BRL 3A cells.