title: Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule.
abstract: N-methyl-D-aspartate receptors (NMDARs) mediate synaptic plasticity, and their dysfunction is implicated in multiple brain disorders. NMDARs can be allosterically modulated by numerous compounds, including endogenous neurosteroid pregnanolone sulfate. Here, we identify the molecular basis of the use-dependent and voltage-independent inhibitory effect of neurosteroids on NMDAR responses. The site of action is located at the extracellular vestibule of the receptor's ion channel pore and is accessible after receptor activation. Mutations in the extracellular vestibule in the SYTANLAAF motif disrupt the inhibitory effect of negatively charged steroids. In contrast, positively charged steroids inhibit mutated NMDAR responses in a voltage-dependent manner. These results, in combination with molecular modeling, characterize structure details of the open configuration of the NMDAR channel. Our results provide a unique opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with dysfunction of the glutamate system.
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Vyklicky
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Krausova
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Cerny
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Ales
authors.initials: A
authors.lastname: Balik
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Zapotocky
authors.affiliation: Charles University in Prague, Faculty of Science, Albertov 6, 128 43 Prague 2, Czech Republic.
authors.forename: Marian
authors.initials: M
authors.lastname: Novotny
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lichnerova
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Smejkalova
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Kaniakova
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Miloslav
authors.initials: M
authors.lastname: Korinek
authors.affiliation: 1] Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic [2] School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, PR1 2HE, UK [3] Institute of Medical Physiology, School of Medicine, University of Belgrade, Visegradska 26/II, 11000 Beograd, Srbija.
authors.forename: Milos
authors.initials: M
authors.lastname: Petrovic
authors.affiliation: Institute of Chemical Technology-Prague, Technicka 5, 166 28 Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Kacer
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Horak
authors.affiliation: Institute of Organic Chemistry and Biochemistry CAS, Flemingovo nam. 2, 166 10 Prague 2, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Chodounska
authors.affiliation: Institute of Physiology CAS, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Vyklicky
mesh_terms: D020816:Amino Acid Motifs; D006801:Humans; D009154:Mutation; D011280:Pregnanolone / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014722:Vestibule, Labyrinth / Q000737:chemistry / Q000378:metabolism
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D011280:Pregnanolone