Transient Receptor Potential Channel Ankyrin-1 Is Not a Cold Sensor for Autonomic Thermoregulation in Rodents

Abstract

The rodent transient receptor potential ankyrin-1 (TRPA1) channel has been hypothesized to serve as a temperature sensor for thermoregulation in the cold. We tested this hypothesis by using deletion of the Trpa1 gene in mice and pharmacological blockade of the TRPA1 channel in rats. In both Trpa1 Ϫ/Ϫ and Trpa1 ϩ/ϩ mice, severe cold exposure (8°C) resulted in decreases of skin and deep body temperatures to ϳ8°C and 13°C, respectively, both temperatures being below the reported 17°C threshold temperature for TRPA1 activation. Under these conditions, Trpa1Ϫ/Ϫ mice had the same dynamics of body temperature as Trpa1 ϩ/ϩ mice and showed no weakness in the tail skin vasoconstriction response or thermogenic response to cold. In rats, the effects of pharmacological blockade were studied by using two chemically unrelated TRPA1 antagonists: the highly potent and selective compound A967079, which had been characterized earlier, and the relatively new compound 43 ((4R)-1,2,3,4-tetrahydro-4-[3-(3-methoxypropoxy)phenyl]-2-thioxo-5H-indeno[1,2-d]pyrimidin-5-one), which we further characterized in the present study and found to be highly potent (IC 50 against cold of ϳ8 nM) and selective. Intragastric administration of either antagonist at 30 mg/kg before severe (3°C) cold exposure did not affect the thermoregulatory responses (deep body and tail skin temperatures) of rats, even though plasma concentrations of both antagonists well exceeded their IC 50 value at the end of the experiment. In the same experimental setup, blocking the melastatin-8 (TRPM8) channel with AMG2850 (30 mg/kg) attenuated cold-defense mechanisms and led to hypothermia. We conclude that TRPA1 channels do not drive autonomic thermoregulatory responses to cold in rodents.

Nasal TRPA1 mediates irritant‐induced bradypnea in mice

“…Also, TRPV1 is well characterized as a heat‐sensing channel, and although TRPA1's role in cold‐sensing is controversial (de Oliveira et al. ), its function in regard to temperature is most likely disparate. Thus, capsaicin application would not necessarily produce the same result as TRPA1 activation.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…In mice, the temperature sensitivity of the TRPA1 channel protein (cold vs. warm) is apparently determined by only three amino acid residues (Jabba et al, 2014); however, the native channel is not involved in autonomic thermoregulation (de Oliveira et al, 2014). It is noteworthy that TRPA1 blockade exerted an anxiolytic-like action in mice (de Moura et al, 2014).…”

Blocking TRPA1 in Respiratory Disorders: Does It Hold a Promise?

“…Unlike TRPV1 or TRPM8, TRPA1 is not involved in body temperature regulation at basal level or under cold challenge [53,54]. Hence TRPA1 antagonists are expected to be devoid of adverse effects on body temperature unlike the TRPV1 antagonists (hyperthermia) or TRPM8 antagonists (hypothermia).…”