TY - JOUR
T1 - Intracellular Calcium Mobilization in Response to Ion Channel Regulators via a Calcium Induced Calcium Release Mechanism
AU - Petrou, Terry
AU - Olsen, Hervor
AU - Thrasivoulou, Christopher
AU - Masters, John R
AU - Ashmore, Jonathan F
AU - Ahmed, Aamir
PY - 2017/2/28
Y1 - 2017/2/28
N2 - 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.
AB - 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.
U2 - 10.1124/jpet.116.236695
DO - 10.1124/jpet.116.236695
M3 - Article
SN - 0022-3565
VL - 360
SP - 378
EP - 387
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -
