Molecular mechanisms of proton conductance and gating in otop proton channels

The National Institute of General Medical Sciences awarded St. John's University, New York, a Project Grant of $562,500 on July 1, 2026, to investigate the molecular mechanisms of proton conductance and gating in OTOP proton channels under the Biomedical Research and Research Training program (CFDA 93.859).

The research will define the proton-conducting pore and selectivity filter of OTOP channels, determine how the N- and C-pores regulate gating, and test whether an OTOP1 monomer represents the minimal functional unit. OTOP channels mediate proton transport across membranes in diverse tissues, including taste receptor cells, vestibular organs, and epithelial cells critical for acid-base balance. Understanding OTOP channel mechanisms will advance ion channel physiology and provide insights into proton transport principles across biological systems.

Work is performed at St. John's University's Jamaica, New York campus. The period of performance runs from July 1, 2026, through June 30, 2029.

Abstract

Proton channels play fundamental roles in maintaining PH homeostasis, membrane potential regulation, and cellular signaling, and their dysfunction contributes to cancer progression, ischemic injury, metabolic imbalance, and sensory disorders. Otopetrins (OTOP1-3) represent a newly identified family of evolutionarily conserved proton-selective ION channels that mediate proton transport across membranes in diverse tissues, including taste receptor cells, vestibular organs, and epithelial cells critical for acid-base balance. The molecular mechanisms that govern otop channel conductance and gating remain largely unknown. Each otop subunit contains two homologous domains (n and c), each forming a barrel-like structure, and the dimeric channel encloses a central, lipid-filled cavity that is structurally stable but likely nonconductive. However, which structural pathway conducts protons and how the two domains regulate gating remain unresolved. Our recent studies reveal that mutations within the intrasubunit interface convert proton selectivity to anion permeability, establishing this region as the primary conduction pathway, while mutations in conserved residues of the n- and c-pores alter gating, producing cation leaks or biphasic activation, implicating these domains in gating regulation rather than conductance. Moreover, putative monomeric OTOP1 mutants retains robust proton current, suggesting that each subunit can function independently. Building on these findings, this project will (1) define the proton-conducting pore and selectivity filter of otop channels, (2) determine how the n- and c-pores regulate gating, and (3) test whether an OTOP1 monomer represents the minimal functional unit. Understanding otop channel mechanisms will advance ION channel physiology and provide new insights into proton transport principles across biological systems. Conducted in an undergraduate- centered research environment, this R15 project will integrate high-impact mechanistic studies with meaningful student participation, fostering the next generation of biomedical scientists.