Thermally activated TRP channels: molecular sensors for temperature detection

Abstract

Temperature sensing is one of the oldest capabilities of living organisms, and is essential for sustaining life, because failure to avoid extreme noxious temperatures can result in tissue damage or death. A subset of members of the transient receptor potential (TRP) ion channel family is finely tuned to detect temperatures ranging from extreme cold to noxious heat, giving rise to thermoTRP channels. Structural and functional experiments have shown that thermoTRP channels are allosteric proteins, containing different domains that sense changes in temperature, among other stimuli, triggering pore opening. Although temperature-dependence is well characterized in thermoTRP channels, the molecular nature of temperature-sensing elements remains unknown. Importantly, thermoTRP channels are involved in pain sensation, related to pathological conditions. Here, we provide an overview of thermoTRP channel activation. We also discuss the structural and functional evidence supporting the existence of an intrinsic temperature sensor in this class of channels, and we explore the basic thermodynamic principles for channel activation. Finally, we give a view of their role in painful pathophysiological conditions.

Disease-associated mutations in TRPM3 render the channel overactive via two distinct mechanisms

“…While the mechanism of temperature activation of TRP channels is not fully understood (Clapham and Miller, 2011;Islas, 2017;Arrigoni and Minor, 2018;Castillo et al, 2018), large scale unbiased mutagenesis studies on TRPV1 (Grandl et al, 2010) and TRPV3 (Grandl et al, 2008) show that mutations in the pore region and the outer portion of S6 in these channels selectively abolished heat-, but not agonist-induced channel activation. The P1090/1092Q mutation in TRPM3 is located in the outer portion of S6, and it had a stronger effect on heat activation than the V990/9992M mutation, therefore it is possible that the primary effect of the P1090/1092Q mutation is increasing heat sensitivity.…”

Increasing Warmth in Adolescents with Anorexia Nervosa: A Randomized Controlled Crossover Trial Examining the Efficacy of Mustard and Ginger Footbaths

“…For GI, this heightened warmth perception endured for 10 minutes after termination of the footbath [12]. e fact that the active ingredients of GI and MU are able to penetrate skin [18][19][20] and to activate temperaturesensitive ion channels of the transient receptor potential (TRP) ion channel superfamily [21][22][23] might explain the potential therapeutic advantage of both thermogenic substances when added to warm footbaths. However, these warming and stimulating effects have so far only been described in healthy adults.…”

Irreversible temperature gating in trpv1 sheds light on channel activation

“…The biophysical response of TRPV1 to temperature change is a large increase in current, produced both by an increase in the channel open probability and in the single channelconductance, with the open probability showing the larger temperature dependence. The mechanism by which these channels accomplish the conversion of the absorbed heat into a conformational change that eventually triggers channel opening remains largely unknown (Castillo et al, 2017).…”