Effects of neramexane, an open channel blocker of NMDA receptors, on the 910 nicotinic receptor.

PLAZAS PV; SAVINO J; GOMEZ-CASATI ME; PARSONS CG; ELGOYHEN AB

Congreso; XLII Reunion Anual de la Sociedad Argentina de Bioquimica y Biologia Molecular; 2006

The aim of this work was to study the effects of neramexane, an uncompetitive NMDA receptor antagonist, on the a9a10 nicotinic receptor (nAChR). cDNAs coding for the rat a9 and a10 subunits were expressed in Xenopus laevis oocytes and agonist-evoked currents were measured under two-electrode voltage-clamp. Electrophysiological recordings in inner hair cells (IHCs) were performed by patch-clamp in acutely excised apical turns of the organ of Corti. The effects of neramexane were compared with those of memantine, a well-studied pore blocker of NMDA receptors. Our results indicate that, in oocytes, both compounds block ACh-evoked responses at micromolar concentrations with similar apparent affinities (neramexane IC50: 0.39 ± 0.03 mM; memantine IC50: 1.2 ± 0.4 mM). Blockage of rat a9a10 by neramexane was voltage-independent while blockage by memantine was slightly voltage-dependent. Neramexane inhibited ACh currents in a mixed competitive and noncompetitive manner. In IHCs, neramexane blocked ACh-evoked responses with an IC50 value (0.3 ± 0.08 mM) similar to that found for recombinant a9a10 receptors. In addition, neramexane blocked responses to synaptically released ACh. Since memantine and neramexane  are effective when administered to animal models for various disease states, our findings suggest that the actions of these compounds at nAChRs may be of therapeutic relevance