Thermal Stability of Phase-Separated Domains in Multicomponent Lipid Membranes with Local Anesthetics

The functional mechanisms of local anesthetics (LAs) have not yet been fully explained, despite their importance in modern medicine. Recently, an indirect interaction between channel proteins and LAs was proposed as follows: LAs alter the physical properties of lipid membranes, thus affecting the channel proteins. To examine this hypothesis, we investigated changes in thermal stability in lipid membranes consisting of dioleoylphosphocholine, dipalmitoylphosphocholine, and cholesterol by adding the LAs, lidocaine and tetracaine. The miscibility temperature of liquid-ordered (L-o) and liquid-disordered (L-d) phase separation was lowered, whereas that of phase separation between solid-ordered (S-o) and L-d phases was unchanged by LAs. Furthermore, we measured the line tension at the L-o/L-d interface from domain boundary fluctuation and found that it was significantly decreased by LAs. Finally, differential scanning calorimetry (DSC) revealed a change in the lipid main transition temperature on the addition of LAs. Based on the DSC measurements, we considered that LAs are partitioned into two coexisting phases.