Selective inhibition of human heteromeric α9α10 nicotinic acetylcholine receptors at a low agonist concentration by low concentrations of ototoxic organic solvents

Abstract

Ethylbenzene and para-xylene (p-xylene), but not the chemically closely related organic solvents ortho-xylene (o-xylene) and meta-xylene (m-xylene), are known to cause ototoxicity and irreversible hearing loss, though the underlying mechanisms are still unknown. In this study, effects of ethylbenzene and of p-, o-, and m-xylene on human heteromeric α9α10 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes were investigated using the two-electrode voltage clamp technique. ACh dose-dependently evoked an α9α10 nAChR-mediated ion current with an EC50 of 137 μM. When ACh is applied at a low concentration (10 μM), the nAChR-mediated ion current is inhibited by a low concentration (10 μM) of ethylbenzene and p-xylene, but not by the same concentration of the non-ototoxic solvents. At a high solvent concentration (300 μM), all solvents cause inhibition of the ion currents evoked by 10 μM ACh. Ion currents evoked by a near maximum-effective concentration ACh (1 mM) are inhibited by the selected organic solvents only at 300 μM. These results demonstrate that low concentrations of the known ototoxic solvents ethylbenzene and p-xylene inhibit α9α10 nAChR-mediated ion currents, whereas the structurally related, non-ototoxic solvents m-xylene and o-xylene do not, indicating that the α9α10 nAChR is a potential target for solvent-induced ototoxicity.