Journal
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 47, Issue 1, Pages 84-96Publisher
ELSEVIER
DOI: 10.1016/j.ejps.2012.05.004
Keywords
AtoSC; Verapamil; Diltiazem; Nifedipine; cPHB; Ca2+-channels blockers
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Verapamil, diltiazem and nifedipine are Ca2+-channel blockers used in cardiovascular diseases. We report here that the Escherichia coli AtoSC signaling is inhibited by those blockers. AtoSC two-component system plays a pivotal role in sophisticated signaling networks in E. coli regulating processes implicated in bacterial homeostasis and pathogenicity. The Ca2+-channel blockers abrogated the in vitro full-length AtoS kinase autophosphorylation. However, they demonstrated no effect on the AtoS cytoplasmic form autophosphorylation. AtoC protected AtoS from verapamil or diltiazem but not from nifedipine, when the two constituents formed complex. The blockers did not affect the AtoS similar to P to AtoC phosphotransfer. The blockers-mediated AtoSC inhibition was verified in vivo on the atoDAEB expression, which was inhibited only in AtoSC-expressing bacteria upon acetoacetate. The AtoS and AtoC protein or their genes transcription levels were unaffected by the blockers. Blockers demonstrated differential effects in the regulation of both the cytosolic- and most potently the membrane-bound-cPHB. Extracellular Ca2+ counteracted the verapamil-mediated effect on cPHB only in atoSC(+) cells. Extracellular Ca2+ reversed the diltiazem-mediated cPHB decreases in cells of both genetic backgrounds, yet a Ca2+-concentration dependent reversion was observed only in the AtoSC-regulated cPHB. Nifedipine caused a more pronounced cPHB down-regulation that was not reversed by extracellular Ca2+. The AtoSC signaling inhibition by Ca2+-channel blockers used for human treatment, and their differential effects on cPHB-formed Ca2+-channels, signify their implications in bacterial-host interactions through the two-component signaling and could stimulate the design of Ca2+-channels blockers derivatives acting as inhibitors of two-component systems. (C) 2012 Elsevier B.V. All rights reserved.
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