Polyamine-like actions of aminoglycosides at recombinant N-methyl-D-aspartate receptors

Recent pharmacological studies have led to the hypothesis that aminoglycosi de-induced ototoxicity is an excitotoxic process mediated, at least in part , by a polyamine-like modulation of N-methyl-D-aspartate (NMDA) receptors. To explore this hypothesis, we compared the effects of several aminoglycosi des (neomycin B, kanamycin A, streptomycin, and dihydrostreptomycin) with s permine on recombinant NMDA receptors of defined composition expressed in X enopus oocytes. Like spermine, aminoglycosides potentiate agonist-induced r esponses in the presence of both saturating glycine ("glycine-independent") and subsaturating glycine ("glycine-dependent") concentrations on NR1A/2B receptors. Likewise, aminoglycosides and spermine potentiated the agonist r esponses under glycine-dependent conditions on NR1A/2A receptors. Despite t hese similarities, several prominent differences were observed between sper mine and aminoglycosides as well as among individual aminoglycosides. For e xample, neomycin B, streptomycin, and kanamycin A, but neither spermine nor dihydrostreptomycin, potentiated glycine-dependent responses on NR1A/2C re ceptors. Differences between spermine and aminoglycosides also were observe d with respect to the voltage dependence of polyamine-like actions. For exa mple, under glycine-dependent conditions, potentiation at NR1A/2B receptors by spermine was voltage dependent, decreasing as the holding potential was changed from -35 to -85 mV; in contrast, potentiation induced by aminoglyc osides at NR1A/2B receptors was voltage independent. No direct relationship s emerged between the effect of an aminoglycoside at a specific NMDA recept or subtype and the ototoxicity of these antibiotics.