抄録
TRPA1 channel is a nonselective cation channel sensitive to various 'pungent' substances including reactive oxygen species (ROS) and thought to be a nociceptor in the primary sensory neurons. Here we have clarified the physiological regulation of TRPA1 activity by prolyl hydroxylation in two animal models; one is hindlimb pain caused by ischemia/reperfusion and the other is oxaliplatin-induced cold hypersensitivity.
An transient ischemia/reperfusion of mouse hindlimb elicited spontaneous licking behavior peaked within 10 min. The licking was inhibited by ROS scavengers, a TRPA1 antagonist, or TRPA1 deficiency. In human TRPA1-expressing cells as well as cultured mouse dorsal root ganglion (DRG) neurons, ROS-evoked TRPA1 response was enhanced after hypoxia (80 mmHg) for 30 min. The hypoxia-induced sensitization to ROS was inhibited in cells expressing a proline-substituted, prolyl hydroxylase (PHD)-resistant TRPA1 mutant (TRPA1-P394A) or by coexpressing an inactive mutant of PHD. Consistently, a PHD inhibitor increased the ROS-evoked licking through TRPA1 activation. Our results suggest that hindlimb ischemia/reperfusion-evoked spontaneous licking, i.e. painful dysesthesia, is caused by ROS-evoked activation of TRPA1 that have been sensitized under hypoxia via inhibition of PHD-mediated prolyl hydroxylation of TRPA1.
Clinically, a platinum-based anticancer agent, oxaliplatin, induces a peculiar cold-triggered peripheral neuropathy within hours after infusion. In mice, a rapid-onset cold hypersensitivity was observed after injection of oxaliplatin, which was ameliorated by blockade or deficiency of TRPA1. The cold hypersensitivity was mimicked by an oxaliplatin metabolite, oxalate, structurally resembling PHD inhibitors. Accordingly, systemic PHD inhibitor induced cold hypersensitivity through TRPA1 sensitization. In human TRPA1-expressing cells, a cold-evoked TRPA1 response was observed in the presence of PHD inhibitor, or in cells expressing TRPA1-P394A mutant, both of which were reduced by ROS scavengers. Taken together, our findings provide evidence that PHD inhibition uncovers TRPA1 sensitization to ROS, which enables TRPA1 to convert ROS signaling into cold sensitivity.
