title: Intracellular Calcium Mobilization in Response to Ion Channel Regulators via a Calcium-Induced Calcium Release Mechanism.
abstract: Free intracellular calcium ([Ca2+]i), in addition to being an important second messenger, is a key regulator of many cellular processes including cell membrane potential, proliferation, and apoptosis. In many cases, the mobilization of [Ca2+]iis controlled by intracellular store activation and calcium influx. We have investigated the effect of several ion channel modulators, which have been used to treat a range of human diseases, on [Ca2+]irelease, by ratiometric calcium imaging. We show that six such modulators [amiodarone (Ami), dofetilide, furosemide (Fur), minoxidil (Min), loxapine (Lox), and Nicorandil] initiate release of [Ca2+]iin prostate and breast cancer cell lines, PC3 and MCF7, respectively. Whole-cell currents in PC3 cells were inhibited by the compounds tested in patch-clamp experiments in a concentration-dependent manner. In all cases [Ca2+]iwas increased by modulator concentrations comparable to those used clinically. The increase in [Ca2+]iin response to Ami, Fur, Lox, and Min was reduced significantly (P < 0.01) when the external calcium was reduced to nM concentration by chelation with EGTA. The data suggest that many ion channel regulators mobilize [Ca2+]iWe suggest a mechanism whereby calcium-induced calcium release is implicated; such a mechanism may be important for understanding the action of these compounds.
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom (T.P., A.A.); Sophion Bioscience A/S, Biolin Scientific, Ballerup, Denmark (H.L.O.); Research Department of Cell and Developmental Biology, The Centre for Cell and Molecular Dynamics (C.T.), Division of Surgery (J.R.M.), and Ear Institute, (J.F.A.), University College London, London, United Kingdom.
authors.forename: Terry
authors.initials: T
authors.lastname: Petrou
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom (T.P., A.A.); Sophion Bioscience A/S, Biolin Scientific, Ballerup, Denmark (H.L.O.); Research Department of Cell and Developmental Biology, The Centre for Cell and Molecular Dynamics (C.T.), Division of Surgery (J.R.M.), and Ear Institute, (J.F.A.), University College London, London, United Kingdom.
authors.forename: Hervør L
authors.initials: HL
authors.lastname: Olsen
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom (T.P., A.A.); Sophion Bioscience A/S, Biolin Scientific, Ballerup, Denmark (H.L.O.); Research Department of Cell and Developmental Biology, The Centre for Cell and Molecular Dynamics (C.T.), Division of Surgery (J.R.M.), and Ear Institute, (J.F.A.), University College London, London, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Thrasivoulou
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom (T.P., A.A.); Sophion Bioscience A/S, Biolin Scientific, Ballerup, Denmark (H.L.O.); Research Department of Cell and Developmental Biology, The Centre for Cell and Molecular Dynamics (C.T.), Division of Surgery (J.R.M.), and Ear Institute, (J.F.A.), University College London, London, United Kingdom.
authors.forename: John R
authors.initials: JR
authors.lastname: Masters
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom (T.P., A.A.); Sophion Bioscience A/S, Biolin Scientific, Ballerup, Denmark (H.L.O.); Research Department of Cell and Developmental Biology, The Centre for Cell and Molecular Dynamics (C.T.), Division of Surgery (J.R.M.), and Ear Institute, (J.F.A.), University College London, London, United Kingdom.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Ashmore
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom (T.P., A.A.); Sophion Bioscience A/S, Biolin Scientific, Ballerup, Denmark (H.L.O.); Research Department of Cell and Developmental Biology, The Centre for Cell and Molecular Dynamics (C.T.), Division of Surgery (J.R.M.), and Ear Institute, (J.F.A.), University College London, London, United Kingdom aamir.ahmed@kcl.ac.uk.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmed
mesh_terms: D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D007700:Kinetics
chemical_list: D007473:Ion Channels; D002118:Calcium