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Role of pertussis toxin‐sensitive G‐proteins in intracellular Ca 2+ release and apoptosis induced by inhibiting cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channels in HepG2 human hepatoblastoma cells
Author(s) -
Kim JungAe,
Kang Young Shin,
Lee Sun Hee,
Lee EunHee,
Lee Yong Soo
Publication year - 2001
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/1097-4644(20010401)81:1<93::aid-jcb1026>3.0.co;2-i
Subject(s) - cystic fibrosis transmembrane conductance regulator , pertussis toxin , glibenclamide , intracellular , g protein , phospholipase c , microbiology and biotechnology , chemistry , apoptosis , biology , pharmacology , endocrinology , signal transduction , biochemistry , gene , diabetes mellitus
Previously, we have reported that inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channels by glibenclamide induced intracellular Ca 2+ release from IP 3 ‐sensitive stores and apoptosis in HepG2 human hepatoblastoma cells (Kim JA, Kang YS, Lee SH, Lee EH, Yoo BH, Lee YS. 1999. Biochem Biophys Res Commun 261:682–688). In this study we investigated the upstream signals involved in the mechanism of these actions of glibenclamide. Treatment with glibenclamide initiated production of inositol 1,4,5‐trisphosphate (IP 3 ) in a dose‐ and time‐dependent manner. The glibenclamide‐induced formation of IP 3 was significantly inhibited by CFTR activators (levamisole and bromotetramisole). The intracellular Ca 2+ release and apoptosis induced by glibenclamide were significantly suppressed by treatment with phospholipase C (PLC) inhibitors (U‐73122 and manoalide) or by pretreatment with pertussis toxin (PTx). In addition, PTx‐catalyzed ADP‐ribosylation of GTP‐binding proteins (G‐proteins) was markedly enhanced by treatment with glibenclamide in a time‐dependent manner. Taken together, these results suggest that PTx‐sensitive G‐proteins coupled to PLCβ may mediate the intracellular Ca 2+ release and apoptosis induced by inhibiting CFTR Cl − channels in HepG2 cells. These results further suggest that the PTx‐sensitive G‐proteins may be a valuable target for the therapeutic intervention of human hepatomas. J. Cell. Biochem. 81:93–101, 2001. © 2001 Wiley‐Liss, Inc.