Molecular Determinants of Temperature Dependent Gating of Ion Channels

Abstract

Physiological sensation of heat or cold in higher organisms is mediated by specialized ion channels whose opening and closing is exquisitely regulated by ambient temperatures. Members of TRP channel family, a branch of the much larger voltage-gated ion channel superfamily, serve as the primary physiological thermo-sensors. However, the physicochemical underpinnings of high temperature-sensitivity of channel gating remain poorly understood. Here, using a heuristic protein design approach, we have transmuted a temperature-insensitive potassium channel into a heat or a cold-sensitive channel. By varying amino acid polarities at sites undergoing state-dependent changes in solvation, we were able to systematically confer temperature-sensing phenotype to a prototypical voltage-dependent potassium channel. We also demonstrate that magnitude of voltage-sensing charges inversely modulate temperature-sensitivity consistent with predictions of thermodynamic coupling. These emerging molecular principles provide a template to understand varied temperature-dependent gating phenotype in channels with conserved transmembrane architecture.