Molecular Basis of Thermal Sensitivity of Heat-Activated Vanilloid Receptor ion Channels

Abstract

In contrast to a hailstorm of information about voltage- or ligand-dependent gating, our knowledge of temperature-driven gating of ion channels is scarce. Temperature-gated channels, as epitomized by thermally active transient receptor potential (TRP) channels, are necessary for thermal sensation, an ability that is vital to survival and conform-seeking of all living organism. Residing at nerve endings underneath skins, these channels figure a role as biological thermometers for perception of ambient temperature. Here we are concerned with the molecular foundations of thermal sensitivity in heat-sensitive vanilloid receptors. We show that, when exposed to rapid temperature jumps, these homologous channels display markedly different activation kinetics and temperature dependence. We construct chimeric channels at strategic positions to delineate contributions of distinct molecular regions of the channels. We identified a cytoplasmic domain to be essential to temperature gating. Alterations of the region were able to fundamentally change the kinetics and temperature dependence of functional wild-types while rescue the heat response of normally temperature-insensitive isoforms. Other regions of the channels, on the other hand, exhibit negligible chimeric effects on the large energetics of thermal gating, suggesting that the gating by temperature in these channels involves localized structural domains for interaction with ambient temperature.