Endogenous neurotoxin-like protein Ly6H inhibits alpha7 nicotinic acetylcholine receptor currents at the plasma membrane

alpha 7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central nervous system and regarded as potential therapeutic targets for neurodegenerative conditions, such as Alzheimer's disease and schizophrenia. Yet, despite the assumed pathophysiological importance of the alpha 7 nAChR, molecular physiological characterization remains poorly advanced because alpha 7 nAChR cannot be properly folded and sorted to the plasma membranes in most mammalian cell lines, thus preventing the analyses in heterologous expression system. Recently, ER-resident membrane protein NACHO was discovered as a strong chaperone for the functional expression of alpha 7 nAChR in non-permissive cells. Ly6H, a brain-enriched GPI-anchored neurotoxin-like protein, was reported as a novel modulator regulating intracellular trafficking of alpha 7 nAChR. In this study, we established cell lines that stably and robustly express surface alpha 7 nAChR by introducing alpha 7 nAChR, Ric-3, and NACHO cDNA into HEK293 cells (Triple alpha 7 nAChR/RIC-3/NACHO cells; TARO cells), and re-evaluated the function of Ly6H. We report here that Ly6H binds with alpha 7 nAChRs on the cell membrane and modulates the channel activity without affecting intracellular trafficking of alpha 7 nAChR.