Species differences and molecular determinant of TRPA1 cold sensitivity

Abstract

TRPA1 is an ion channel and has been proposed as a thermosensor across species. In invertebrate and ancestral vertebrates such as fly, mosquito, frog, lizard and snakes, TRPA1 serves as a heat receptor, a sensory input utilized for heat avoidance or infrared detection. However, in mammals, whether TRPA1 is a receptor for noxious cold is highly controversial, as channel activation by cold was observed by some groups but disputed by others. Here we attribute the discrepancy to species differences. We show that cold activates rat and mouse TRPA1 but not human or rhesus monkey TRPA1. At the molecular level, a single residue within the S5 transmembrane domain (G878 in rodent but V875 in primate) accounts for the observed difference in cold sensitivity. This residue difference also underlies the species-specific effects of menthol. Together, our findings identify the species-specific cold activation of TRPA1 and reveal a molecular determinant of cold-sensitive gating.

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

“…2010; Chen et al. 2013). The rodent findings suggest that inhibiting abnormal small‐diameter primary afferent activity could be useful in the treatment of oxaliplatin‐induced neuropathic pain.…”

“…2011; Chen et al. 2013; Hirai and Hama 2014). The species difference in molecular biology could be one reason for the disconnection between significant efficacy observed in rodent models of oxaliplatin‐induced neuropathic pain and the failure to replicate efficacy in patients.…”

“…2012; Chen et al. 2013). Nonhuman primates (NHP) are a favored species in neuroscience research because of their complex neuroanatomy, compared to that of rodents, and their expression of clinically relevant symptoms in neurological disorders such as in Parkinson's disease (Courtine et al.…”

Neurophysiology of Skin Thermal Sensations

“…Recent investigations on the temperature sensitivity of TRPA1 across different species (46) have indeed shown that the temperature sensitivity of TRPA1 could be species-dependent, as a result of an evolutionary divergence driven by different requirements for survival (189).…”

“…In their recent work, Chen et al (46) have shown that the TRPA1 ion channel can alternatively be a heat sensitive channel in invertebrates and ancestral invertebrates (e.g. fly and snakes), a noxious cold sensitive channel in rat and mouse, and a temperature insensitive channel in human and rhesus monkey.…”