A Model where Anesthetic Effects on Ion Channels are Mediated by a Critical Membrane

Abstract

Diverse molecules induce general anesthesia with potency strongly correlated both with their hydrophobicity and their effects on certain ion channels. We recently observed that several n-alcohol anesthetics inhibit heterogeneity in plasma membrane derived vesicles by lowering the critical temperature (Tc) for phase separation. Furthermore, rare treatments that reverse anesthetic effects, including high hydrostatic pressure, actually raise Tc, reversing anesthetic effects on membrane critical temperatures (Machta et. al., Biophys J , 111:3, (2016)). We will present a model in which ion channels are regulated by the nearly critical membrane in which they are embedded, and where anesthetics interfere with and mimic this regulation. In our model, ion channels are allosterically coupled to Ising composition modes. We use a mix of Monte-Carlo and exact numerical techniques to show that this type of regulation has several surprising features (Kimchi et. al., ArXiV 1607.06836, (2016)). Owing to diverging generalized susceptibilities, such a channel's activity becomes strongly influenced by perturbations that influence the critical temperature, in a manner that can, in principle, quantitatively account for changes in channel gating that accompany addition of anesthetics. In addition, the channel's kinetics acquire a range of time scales from its surrounding membrane, naturally leading to non-Markovian dynamics.