title: Direct inhibition of N-methyl-D-aspartate (NMDA)-receptor function by antiglaucomatous beta-antagonists.
abstract: In the present study, we investigated the direct effects of antiglaucoma drugs (timolol, betaxolol, pilocarpine, and latanoprost) on N-methyl-D-aspartate (NMDA)-receptor function using a Xenopus oocytes expression system and electrophysiological techniques. In oocytes expressing wild-type NMDA (NR1a/NR2A) receptors, timolol and betaxolol significantly inhibited glutamate-evoked currents, whereas less inhibition was obtained with pilocarpine, and latanoprost had few effects. Moreover, the effect of timolol and betaxolol was noncompetitive with respect to glutamate. Mutations that changed Asn616 of the NR1a subunit, a critical residue for Mg(2+) blocking of NMDA receptors, to Arg (N616R) or Gln (N616Q) almost eliminated the inhibitory effects of timolol and betaxolol, as well as the blocking effect of Mg(2+). Experiments were also carried out to examine the protective effects of timolol and betaxolol against death of oocytes expressing NMDA receptors. During incubation of oocytes, especially in Mg(2+)-free medium, cell death was induced by addition of glutamate because of the continuous activation of the NMDA receptors expressed. Timolol and betaxolol significantly improved oocyte viability when they were added during the incubation period. These results suggest that timolol and betaxolol may have an additional role that they directly inhibit NMDA-receptor function, possibly via N616 of the NR1a subunit.
authors.affiliation: Department of Ophthalmology, School of Medicine, University of Occupational and Environmental Health, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nagata
authors.forename: Susumu
authors.initials: S
authors.lastname: Ueno
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Morita
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kubota
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tawara
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D015784:Betaxolol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005901:Glaucoma / Q000188:drug therapy*; D008274:Magnesium / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D013999:Timolol / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D000319:Adrenergic beta-Antagonists; D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D013999:Timolol; D008274:Magnesium; D015784:Betaxolol; D002118:Calcium