Abstract
Temperature influences dynamics and state-equilibrium distributions in all molecular processes, and only a relatively narrow range of temperatures is compatible with life-organisms must avoid temperature extremes that can cause physical damage or metabolic disruption. Animals evolved a set of sensory ion channels, many of them in the family of transient receptor potential cation channels that detect biologically relevant changes in temperature with remarkable sensitivity. Depending on the specific ion channel, heating or cooling elicits conformational changes in the channel to enable the flow of cations into sensory neurons, giving rise to electrical signaling and sensory perception. The molecular mechanisms responsible for the heightened temperature-sensitivity in these ion channels, as well as the molecular adaptations that make each channel specifically heat- or cold-activated, are largely unknown. It has been hypothesized that a heat capacity difference (ΔC(p)) between two conformational states of these biological thermosensors can drive their temperature-sensitivity, but no experimental measurements of ΔC(p) have been achieved for these channel proteins. Contrary to the general assumption that the ΔC(p) is constant, measurements from soluble proteins indicate that the ΔC(p) is likely to be a function of temperature. By investigating the theoretical consequences for a linearly temperature-dependent ΔC(p) on the open-closed equilibrium of an ion channel, we uncover a range of possible channel behaviors that are consistent with experimental measurements of channel activity and that extend beyond what had been generally assumed to be possible for a simple two-state model, challenging long-held assumptions about ion channel gating models at equilibrium.