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Intracellular Calcium Mobilization in Response to Ion Channel Regulators via a Calcium Induced Calcium Release Mechanism

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Terry Petrou, Hervor Olsen, Christopher Thrasivoulou, John R Masters, Jonathan F Ashmore, Aamir Ahmed

Original languageEnglish
Pages (from-to)378-387
Number of pages32
JournalJournal of Pharmacology and Experimental Therapeutics
Volume360
Issue number2
Early online date19 Jan 2017
DOIs
Accepted/In press14 Nov 2016
E-pub ahead of print19 Jan 2017
Published28 Feb 2017

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Abstract

Free intracellular calcium ([Ca2+]i), in addition to being an important second messenger, is a key regulator of many cellular processes including the cell membrane potential, proliferation and apoptosis. In many cases, the mobilization of [Ca2+]i is 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+]i release, by ratiometric calcium imaging. We show that six such modulators (Amiodarone (Ami), Dofetilide (Dof), Furosemide (Fur), Minoxidil (Min), Loxapine (Lox), and Nicorandil (Nic)) initiate release of [Ca2+]i in 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+]i was increased by modulator concentrations comparable to those used clinically. The increase in [Ca2+]i in 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+]i. We suggest a mechanism whereby calcium induced calcium release is implicated; such a mechanism may be important for understanding the action of these compounds.

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