Stimulatory and inhibitory properties of aminoglycoside antibiotics at N-methyl-D-aspartate receptors

Citation
T. Masuko et al., Stimulatory and inhibitory properties of aminoglycoside antibiotics at N-methyl-D-aspartate receptors, J PHARM EXP, 290(3), 1999, pp. 1026-1033
Citations number
36
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
290
Issue
3
Year of publication
1999
Pages
1026 - 1033
Database
ISI
SICI code
0022-3565(199909)290:3<1026:SAIPOA>2.0.ZU;2-E
Abstract
The effects of aminoglycoside antibiotics on N-methyl-D-aspartate (NMDA) re ceptors were studied using voltage-clamp recording of recombinant NMDA rece ptors expressed in Xenopus oocytes. A number of aminoglycosides were found to potentiate macroscopic currents at heteromeric NR1A/NRPB 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 kasu gamycin and spectinomycin. The degree of stimulation paralleled the number of the amino groups in the aminoglycosides. The stimulatory effects of amin oglycosides were move pronounced at subsaturating concentrations of glycine and at acidic pH, similar to the stimulatory effects of spermine. We measu red the effects of aminoglycosides at mutant NMDA receptors to determine wh ich amino acid residues in NMDA receptor subunits are involved in stimulati on. Mutations that reduced or abolished spermine stimulation also reduced s timulation by aminoglycosides. Several aminoglycosides produced a weak volt age-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 r esults suggest that aminoglycosides having more than three amino groups hav e stimulatory effects that are mediated through the spermine-binding site o n NMDA receptors.