The biophysical and molecular basis of TRPV1 proton gating

Abstract

The capsaicin receptor TRPV1, a member of the transient receptor potential family of non-selective cation channels is a polymodal nociceptor. Noxious thermal stimuli, protons, and the alkaloid irritant capsaicin open the channel. The mechanisms of heat and capsaicin activation have been linked to voltage-dependent gating in TRPV1. However, until now it was unclear whether proton activation or potentiation or both are linked to a similar voltagedependent mechanism and which molecular determinants underlie the proton gating. Using the whole-cell patchclamp technique, we show that protons activate and potentiate TRPV1 by shifting the voltage dependence of the activation curves towards more physiological membrane potentials. We further identified a key residue within the pore region of TRPV1, F660, to be critical for voltage-dependent proton activation and potentiation. We conclude that proton activation and potentiation of TRPV1 are both voltage dependent and that amino acid 660 is essential for proton-mediated gating of TRPV1.

Intracellular Proton-mediated Activation of TRPV3 Channels Accounts for the Exfoliation Effect of α-Hydroxyl Acids on Keratinocytes

“…Cell acidification can serve as a concomitant of cell death (63) and a means to detect painful conditions, especially in deep tissues where the temperature is expected to remain constant (64). A number of TRP channels have been shown to be quite sensitive to changes in extracellular pH (65,66). Although intracellular acidification-mediated inhibition has been observed in TRPV5 and TRPM2 channels (67,68), our findings represent the first demonstration of intracellular acidification-mediated activation by a member of the TRPV channel family.…”

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

“…For example, amino acid F660 has recently been identified as essential for the protonmediated gating of TRPV1 (ref. 48).…”

Novel Methodology to Identify TRPV1 Antagonists Independent of Capsaicin Activation

“…13,29 An allosteric model to describe the synergy between voltage gating and other independent stimuli to regulate channel gating has already been described. 30 Several molecular determinants responsible for the proton-and heat-dependent shifts in the voltage dependence of activation have been described, including F660 31 in the S6 transmembrane domain and I696, W697, and Q700 in the TRP box. 32 It would be interesting to assess the types of molecular interactions the compounds identified here have with TRPV1 and determine if they have a better profile than some of the previous TRPV1 antagonists, particularly with respect to causing hyperthermia in vivo.…”