Abstract
Lithium imposes several cellular effects allegedly through multiple physiological mechanisms. Membrane depolarization is a potential unifying concept of these mechanisms. Multiple inherent imperfections of classical electrophysiology limit its ability to fully explain the depolarizing effect of lithium ions; these include incapacity to explain the high resting permeability of lithium ions, the degree of depolarization with extracellular lithium concentration, depolarization at low therapeutic concentration, or the differences between the two lithium isotopes Li-6 and Li-7 in terms of depolarization. In this study, we implemented a mathematical model that explains the quantum tunneling of lithium ions through the closed gates of voltage-gated sodium channels as a conclusive approach that decodes the depolarizing action of lithium. Additionally, we compared our model to the classical model available and reported the differences. Our results showed that lithium can achieve high quantum membrane conductance at the resting state, which leads to significant depolarization. The quantum model infers that quantum membrane conductance of lithium ions emerges from quantum tunneling of lithium through the closed gates of sodium channels. It also differentiates between the two lithium isotopes (Li-6 and Li-7) in terms of depolarization compared with the previous classical model. Moreover, our study listed many examples of the cellular effects of lithium and membrane depolarization to show similarity and consistency with model predictions. In conclusion, the study suggests that lithium mediates its multiple cellular effects through membrane depolarization, and this can be comprehensively explained by the quantum tunneling model of lithium ions.