Effect of the antidepressant sertraline on Ca~(2+)fluxes in Madin-Darby canine renal tubular cells

摘要

The effect of the antidepressant sertraline on cytosolic-free Ca~(2+) concentrations ([Ca~(2+)i) in Madin Darby canine kidney (MDCK) cells is unclear. This study explored whether sertraline changed basal [Ca~(2+)]i levels in suspended MDCK cells by using fura-2 as a Ca~(2+)-sensitive fluorescent dye. Sertraline at concentrations between land 100 μM increased [Ca~(2+)]i in a concentration-dependent manner. The Ca~(2+) signal was reduced partly by removing extracellular Ca~(2+) implicating Ca~(2+) entry and release both contributed to the [Ca~(2+)]i rise. Sertraline induced Mn2+ influx, leading to quench of fura-2 fluorescence, suggesting Ca~(2+) influx. This Ca~(2+) influx was inhibited by suppression of phospholiapase A2 but not by store-operated Ca~(2+) channel blockers and protein kinase C/A modulators. In Ca~(2+)-free medium, pretreatment with the endoplasmic reticulum Ca~(2+) pump inhibitors nearly abolished sertraline-induced Ca~(2+) release. Conversely, pretreatment with sertraline partly reduced inhibitor-induced [Ca~(2+)]i rise, suggesting that sertraline released Ca~(2+) from endoplasmic reticulum. Inhibition of phospholipase C did not much alter sertraline-induced [Ca~(2+)]i rise. Collectively, in MDCK cells, sertraline induced [Ca~(2+)]i rises by causing phospholipase C-independent Ca~(2+) release from the endoplasmic reticulum and Ca~(2+) influx via phos-pholipase A2-sensitive Ca~(2+) channels.