Proton Signaling Biology From Ancient Bioenergetics to Neural Communication: An Exploration of Keratan Sulfate as a Potential Proton-Modulatory Molecule

This mini review examines the potential roles of proton signaling in the peripheral and central nervous systems and its proposed regulation by keratan sulfate (KS). Protons are central to bioenergetics and rapid chemical signaling, linking metabolism to membrane excitability and receptor activity across tissues. Nanoscale-to-microscale pH transients may add a further layer of intercellular communication in the nervous system through proton-sensitive ion channels and receptors. Extracellular matrix glycosaminoglycans may influence this signaling by buffering and transporting protons. Keratan sulfate has an unusually high capacity to bind and conduct protons. Evidence from electrolocation biology, proton-conductive biomaterials, and brain proton sensors suggests that keratan sulfate may act as a local proton reservoir and shuttle within defined microenvironments, thereby shaping pH-dependent neuromodulatory processes in health and disease. KS-substituted proteoglycans have the potential to act as neuron modulatory molecules mediating effects on cellular metabolism. KS shows considerable promise as a neuromodulatory molecule. Further electrophysiological studies are warranted using KS knockout animal models to test this hypothesis and validate the proposed role of KS as a potential regulatory neural interface molecule.