Transient receptor potential ankyrin type 1 (TRPA1) channel, a new target for the antimalarial artemisinin

The molecular mechanism of the antimalarial artemisinin and its derivatives is not yet fully understood, although these compounds are successfully used against Plasmodium protists. Other biological effects (anti-cancer or antinociceptive effects) are also possible following administration of artemisinin. Considering that Transient Receptor Potential (TRP) ion channels are key signalling molecules in many cancer and pain pathways, the aim of this study was to test whether members of this family are among the molecular targets of artemisinin. The effect of artemisinin on wild type or mutant TRP channels, expressed in native or heterologous system, was investigated using calcium microfluorimetry and the patch clamp technique together with pharmacological tools. Acute exposure of HEK293t cells expressing human TRPA1 to artemisinin induced calcium transients which were concentration dependent and were abolished by the selective TRPA1 antagonist A967079. Also, in the same heterologous system, artemisinin induced inwardly-rectifying whole cell currents which were again inhibited by A967079. Moreover, we compared the calcium transients activated by artemisinin and two TRPA1 agonists in HEK293t cells transfected with wild type human TRPA1 to those initiated in HEK293t expressing mutant TRPA1: C621S/C641S/C665S (insensitive to electrophilic agonists) and S873V/T874L (insensitive to non-electrophilic agonists), respectively. Our results suggest that artemisinin and carvacrol (non-electrophilic) have similar mechanism of activation of TRPA1. Finally, artemisinin induced calcium signals in a subpopulation of mouse cultured DRG neurons, most likely mediated by TRPA1. In conclusion, artemisinin selectively activates the polymodal receptor channel TRPA1 in a manner similar to non-electrophilic agonists.