Temperature Dependence of Mutant Vanilloid Receptor (tRPV) Channels

Abstract

Temperature-gated transient receptor potential (TRP) channels exhibit exceedingly large energetic changes in activation. However, the source of energy and its structural basis are not known. Several studies have recently suggested that the pore domain of the channels plays an essential role in temperature gating. In particular, multiple mutations in the outer pore of the TRPV3 channel, which is activated by heat above 30oC, were found to selectively abrogate the heat response of the channel while leaving the response to chemical agonists largely intact. Vanilloid receptors (TRPV) have a membrane topology resembling that of voltage-gated ion channels, and these mutant residues are located at the S6-linker region. The profound and yet selective effects of the region on thermal sensitivity of TRPV3 suggest that the outer pore of the channel may be responsible for heat sensing. In support of the hypothesis, the replacement of a pore turret region in TRPV1 by a glycine-based fragment was also shown to specifically eliminate the heat sensitivity of the channel without compromising its capsaicin response. Alternatively, the “heat sensors” of the channels, if any, may reside elsewhere, while the pore domain is involved in the downsteam pathway of activation such as allosteric coupling between the heat sensors and the gate of the channel. In this study, we will attempt to discern such two mechanisms. We will show the remaining of temperature dependence in the mutant channels and explore mechanisms and the role of the pore domain in temperature gating.