Memantine inhibits efferent cholinergic transmission in the cochlea by blocking nicotinic acetylcholine receptors of outer hair cells

Memantine is a blocker of Ca2+-permeable glutamate and nicotinic acetylchol ine receptors (nAChR). We investigated the action of memantine on cholinerg ic synaptic transmission at cochlear outer hair cells (OHCs). At this inhib itory synapse, hyperpolarization of the postsynaptic cell results from open ing of SK-type Ca2+-activated K+ channels via a highly Ca2+-permeable nAChR containing the alpha9 subunit. We show that inhibitory postsynaptic curren ts recorded from OHCs were reversibly blocked by memantine with an IC50 val ue of 16 muM. RT-PCR revealed that a newly cloned nAChR subunit, alpha 10, is expressed in OHCs. In contrast to homomeric expression, coexpression of alpha9 and alpha 10 subunits in Xenopus laevis oocytes resulted in robust a cetylcholine-induced currents, indicating that the OHC nAChR may be an alph a9/alpha 10 heteromer. Accordingly, nAChR currents evoked by application of the ligand to OHCs and currents through alpha9/alpha 10 were blocked by me mantine with a similar IC50 value of about 1 muM. Memantine block of alpha9 /alpha 10 was moderately voltage dependent. The lower efficacy of memantine for inhibition of inhibitory postsynaptic currents (IPSCs) most probably r esults from a blocking rate that is slow with respect to the short open tim e of the receptor channels during an IPSC. Thus, synaptic transmission in O HCs is inhibited by memantine block of Ca2+ influx through nAChRs. Importan tly, prolonged receptor activation and consequently massive Ca2+ influx, as might occur under pathological conditions, is blocked at low micromolar co ncentrations, whereas the fast IPSCs initiated by short receptor activation are only blocked at concentrations above 10 muM.