Antidepressants Are Poor Inhibitors of Heat-Evoked Ion Currents Mediated by TRPM2

The heat and redox-sensitive ion channel TRPM2 was reported to be a causative mechanism for depression in a mouse model and to be upregulated in the hippocampus in patients suffering from depressive disorders. TRPM2 may thus be a novel target for antidepressants, but so far, selective TRPM2-inhibitors have not yet been developed. In this in vitro study, we examined the inhibitory effects of several established antidepressants on heat-evoked inward currents of TRPM2.

Human (h) TRPM2 expressed in HEK293 cells was examined by means of whole-cell patch clamp recordings. Effects of duloxetine, amitriptyline, sertraline, fluoxetine, paroxetine, citalopram, escitalopram, ketamine, pregabalin, lidocaine, and QX-314 were explored on heat-evoked currents in cells pretreated with ADP-ribose (ADPR).

While inward currents induced by 1 mM ADPR in the pipette solution displayed a strong rundown hampering pharmacological experiments, heat-evoked currents in cells loaded with 200 μM APDR remained stable upon repetitive activation. Among all substances examined, only inhibition induced by duloxetine displayed a clear concentration-dependency. Thirty micromolar duloxetine was required for 50% inhibition, the same degree of inhibition was also induced by 30 μM amitriptyline, fluoxetine, and paroxetine. While citalopram, escitalopram, ketamine, and pregabalin failed to robustly modify TRPM2, sertraline and low concentrations of lidocaine even potentiated heat-evoked currents.

Our data indicate that some, but not all established antidepressants inhibit hTRPM2 when it is activated by heat and ADPR in vitro, e.g., presumably relevant endogenous agonists. However, none of the examined substances exhibited a potent inhibition which is likely to translate into a clinically relevant effect at effective plasma concentrations. Whether or not TRPM2 may be a relevant target for antidepressants cannot be conclusively assessed by a single in vitro study, thus further studies are required along these lines. Nevertheless, future studies may get simplified by the novel approach we developed for in vitro pharmacological analysis of TRPM2.