TRPA1 gene variants hurting our feelings

TRPA1 is a Ca²⁺-permeable, non-selective cation channel that is activated by thermal and mechanical stimuli, an amazing variety of potentially noxious chemicals, and by endogenous molecules that signal tissue injury. The expression of this channel in nociceptive neurons and epithelial cells puts it at the first line of defense and makes it a key determinant of adaptive protective behaviors. For the same reasons, TRPA1 is implicated in a wide variety of disease conditions, such as acute, neuropathic, and inflammatory pains, and is postulated to be a target for therapeutic interventions against acquired diseases featuring aberrant sensory functions. The human TRPA1 gene can bare mutations that have been associated with painful conditions, such as the N855S that relates to the rare familial episodic pain syndrome, or others that have been linked to altered chemosensation in humans. Here, we review the current knowledge on this field, re-evaluating some available functional data, and pointing out the aspects that in our opinion require attention in future research. We make emphasis in that, although the availability of the human TRPA1 structure provides a unique opportunity for further developments, far more classical functional studies using electrophysiology and analysis of channel gating are also required to understand the structure-function relationship of this intriguing channel.