Vol. 290, Issue 3, 1026-1033, September 1999

Stimulatory and Inhibitory Properties of Aminoglycoside Antibiotics at N-Methyl-D-Aspartate Receptors¹

Takashi Masuko, Tomoko Kuno, Keiko Kashiwagi, Tadashi Kusama, Keith Williams and Kazuei Igarashi

Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan (T.M., T.Kun., K.K., K.I.); College of Pharmacy, Nihon University, Funabashi, Japan (T.Kus.); and Department of Physiology and Pharmacology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York (K.W.)

The effects of aminoglycoside antibiotics on N-methyl-D-aspartate (NMDA) receptors were studied using voltage-clamp recording of recombinant NMDA receptors expressed in Xenopus oocytes. A number of aminoglycosides were found to potentiate macroscopic currents at heteromeric NR1A/NR2B receptors, but not at NR1A/NR2A, NR1A/NR2C, NR1A/NR2D, or NR1B/NR2B receptors. The degree of potentiation had a rank order neomycin B > paromomycin > gentamicin C > geneticin > kanamycin A > streptomycin. Potentiation was not seen with kasugamycin and spectinomycin. The degree of stimulation paralleled the number of the amino groups in the aminoglycosides. The stimulatory effects of aminoglycosides were more pronounced at subsaturating concentrations of glycine and at acidic pH, similar to the stimulatory effects of spermine. We measured the effects of aminoglycosides at mutant NMDA receptors to determine which amino acid residues in NMDA receptor subunits are involved in stimulation. Mutations that reduced or abolished spermine stimulation also reduced stimulation by aminoglycosides. Several aminoglycosides produced a weak voltage-dependent block of NMDA receptors, but the degree of inhibition did not appear to correlate with the number of amino groups in the molecule. The results suggest that aminoglycosides having more than three amino groups have stimulatory effects that are mediated through the spermine-binding site on NMDA receptors.