Contribution of the Putative Inner-Pore Region to the Gating of the Transient Receptor Potential Vanilloid Subtype 1 Channel (TRPV1)

Abstract

The transient receptor potential vanilloid receptor-1 (TRPV1) is a sensory neuron-specific nonselective cation channel that is gated in response to various noxious stimuli: pungent vanilloids, low pH, noxious heat, and depolarizing voltages. By its analogy to K ϩ channels, the S6 inner helix domain of TRPV1 (Y666-G683) is a prime candidate to form the most constricted region of the permeation pathway and might therefore encompass an as-yet-unmapped gate of the channel. Using alanine-scanning mutagenesis, we identified 16 of 17 residues, that when mutated affected the functionality of the TRPV1 channel with respect to at least one stimulus modality. T670A was the only substitution producing the wild-type channel phenotype, whereas Y666A and N676A were nonfunctional but present at the plasma membrane. The periodicity of the functional effects of mutations within the TRPV1 inner pore region is consistent with an ␣-helical structure in which T670 and A680 might play the roles of two bending "hinges."

Investigation of the transient receptor potential vanilloid 1 (TRPV1) ion channel

“…A specific aim of this study, therefore was the determination of the potential loss/gain of sensations that RTX-mediated molecular surgery may cause. shown by others, too [167,175]. To dissect potential side-effect(s) of molecular neurosurgery in vivo, mice were treated with RTX either at birth or at adult age, the resulting changes in behavioral, cellular and molecular biomarkers (i.e.…”

“…[ 169,175,176,178,197] I672 A Its mutation reduced CAPS sensitivity, heat-induced current responses and heatpotentiated CAPS currents.…”

“…Its mutation also reduced CAPS sensitivity, heat-induced current responses and heat-potentiated CAPS currents. [175,177] L674 A Its mutation reduced CAPS sensitivity, heat-induced current responses and heatpotentiated CAPS currents.…”

“…[175] N676 A, F Its mutation influenced the ability of CAPS and RTX to activate TRPV1 without changing the response of the channel to protons. Its mutation to Ala resulted in nonfunctional channel.…”

“…[ 166,175] M677 A Its mutation in a triple mutant (N676F/M677A/L678P) influenced the ability of CAPS and RTX to activate TRPV1 without changing the response of the channel to protons. Its mutation alone blunted heat-induced current responses without a significant change of CAPS-or heat-potentiated CAPS currents.…”