Amitriptyline is a widely used tricyclic antidepressant, which acts primarily as a serotonin-norepinephrine reuptake inhibitor. This study examined the effect of amitriptyline on Ca homeostasis and its related mechanism in MG63 human osteosarcoma cells. Amitriptyline evoked cytosolic-free Ca concentrations ([Ca]) rises concentration dependently. Amitriptyline-evoked Ca entry was confirmed by Mn-induced quench of fura-2 fluorescence. This entry was inhibited by Ca entry modulators nifedipine, econazole, SKF96365, the protein kinase C (PKC) activator phorbol 12-myristate 13 acetate but was not affected by the PKC inhibitor GF109203X. In Ca-free medium, treatment with the endoplasmic reticulum Ca pump inhibitor thapsigargin (TG) inhibited amitriptyline-evoked [Ca] rises by 95%. Conversely, treatment with amitriptyline abolished TG-evoked [Ca] rises. Inhibition of phospholipase C (PLC) with U73122 inhibited amitriptyline-evoked [Ca] rises by 70%. Amitriptyline killed cells at 200-500 μM in a concentration-dependent fashion. Chelating cytosolic Ca with 1,2-bis(2-aminophenoxy)ethane- N, N, N', N'-tetraacetic acid/AM did not reverse amitriptyline-induced cytotoxicity. Collectively, our data suggest that in MG63 cells, amitriptyline induced [Ca] rises by evoking PLC-dependent Ca release from the endoplasmic reticulum and Ca entry via PKC-regulated store-operated Ca entry. Amitriptyline also induced Ca-disassociated cell death.
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