Lee's "Transmembrane Electrostatically-Localized Proton" model does NOT offer a better understanding of neuronal transmembrane potentials.

Abstract

Recently, in a paper entitled "Protonic conductor: Better understanding [sic] neural resting and action potential," Lee applied his Transmembrane Electrostatically-Localized Protons (TELP) hypothesis to neuronal signaling. He stated that Hodgkin's cable theory "could not fully explain the different conductive patterns in unmyelinated and myelinated nerves," whereas his TELP hypothesis "enables much better understanding of neural resting/action potential and [the biological significance of] axon myelination…" However, Lee's TELP hypothesis predicts that under resting conditions, the neuron "accumulat[es] excess negative charge (anions) inside," whereas resting chloride gradients actually feature excess Cl- outside of the cell. Experiments on the neuron have shown that raising external [K+] and decreasing external [Cl-] cause membrane potential depolarization, which is predicted by the Goldman equation, but opposite to TELP hypothesis predictions. Finally, based on his TELP hypothesis, Lee predicted that the main purpose of myelin is to insulate the axonal plasma membrane specifically against proton permeability. However, he cited literature showing that myelin contains proteins that may "serve as a proton conductor with the localized protons." Thus, we show here that Lee's TELP hypothesis is highly problematic, and does NOT offer a "better understanding" of neuronal transmembrane potentials.NEW & NOTEWORTHY In this manuscript I critique a 2020 J. Neurophysiol. paper by James W. Lee. His TELP hypothesis 1) mispredicts the resting neuron's excess of external chloride; 2) predicts the preponderance of surface H+ over Na+ using ΔG° rather than ΔG; 3) mispredicts the dependence of the neuronal resting potential on external [Na+], [K+], and [Cl-]; 4) neither cites experimental results nor proposes experiments to test his hypothesis; and 5) presents a problematic characterization of the purpose of myelin.