PubMed:28533163 JSONTXT

{"project":"kaiyin_test","denotations":[{"id":"T7","span":{"begin":140,"end":156},"obj":"PosReg"},{"id":"T6","span":{"begin":157,"end":166},"obj":"Var"},{"id":"T5","span":{"begin":170,"end":176},"obj":"Gene"},{"id":"T3","span":{"begin":271,"end":297},"obj":"Disease"},{"id":"T4","span":{"begin":309,"end":325},"obj":"Disease"}],"relations":[{"id":"R1","pred":"CauseOf","subj":"T6","obj":"T7"},{"id":"R2","pred":"ThemeOf","subj":"T3","obj":"T7"},{"id":"R3","pred":"ThemeOf","subj":"T4","obj":"T7"},{"id":"R4","pred":"ThemeOf","subj":"T5","obj":"T6"}],"text":"GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors.\nDe novo gain of function mutations in GRIN2B encoding the GluN2B subunit of the N-methyl-d-aspartate (NMDA) receptor have been linked with epileptic encephalopathies, including infantile spasms. We investigated the effects of radiprodil, a selective GluN2B negative allosteric modulator and other non-selective NMDA receptor inhibitors on glutamate currents mediated by NMDA receptors containing mutated GluN2B subunits. The experiments were performed in Xenopus oocytes co-injected with the following human mRNAs: GRIN1/GRIN2B, GRIN1/GRIN2B-R540H, GRIN1/GRIN2B-N615I and GRIN1/GRIN2B-V618G. Glutamate displayed slightly increased potency in the R540H variant, but not in N615I and V618G variants. However, the inhibition by Mg(2+) was completely abolished in N615I and V618G variants. In fact, Mg(2+) enhanced glutamate responses in those variants. The potency of radiprodil to block glutamate-evoked currents was not affected in any of the variants, while the effects by non-selective NMDA inhibitors were greatly reduced in some of the variants. Additionally, in the Mg(2+) insensitive variants, radiprodil blocked glutamate-activated currents with the same potency as in the absence of Mg(2+). The gain of function observed in the reported GRIN2B variants could be a key pathophysiological factor leading to neuronal hyper-excitability in epileptic encephalopathies. The GluN2B-selective inhibitor radiprodil fully retained its pharmacological profile under these conditions, while other non-selective NMDA receptor antagonists lost their potency. Consequently, our data suggest that radiprodil may be a valuable therapeutic option for treatment of pediatric epileptic encephalopathies associated with GRIN2B mutations."}

{"project":"name_no","denotations":[{"id":"T7","span":{"begin":140,"end":156},"obj":"PosReg"},{"id":"T6","span":{"begin":157,"end":166},"obj":"Var"},{"id":"T5","span":{"begin":170,"end":176},"obj":"Gene"},{"id":"T3","span":{"begin":271,"end":297},"obj":"Disease"},{"id":"T4","span":{"begin":309,"end":325},"obj":"Disease"}],"relations":[{"id":"R1","pred":"CauseOf","subj":"T6","obj":"T7"},{"id":"R2","pred":"ThemeOf","subj":"T3","obj":"T7"},{"id":"R3","pred":"ThemeOf","subj":"T4","obj":"T7"},{"id":"R4","pred":"ThemeOf","subj":"T5","obj":"T6"}],"text":"GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors.\nDe novo gain of function mutations in GRIN2B encoding the GluN2B subunit of the N-methyl-d-aspartate (NMDA) receptor have been linked with epileptic encephalopathies, including infantile spasms. We investigated the effects of radiprodil, a selective GluN2B negative allosteric modulator and other non-selective NMDA receptor inhibitors on glutamate currents mediated by NMDA receptors containing mutated GluN2B subunits. The experiments were performed in Xenopus oocytes co-injected with the following human mRNAs: GRIN1/GRIN2B, GRIN1/GRIN2B-R540H, GRIN1/GRIN2B-N615I and GRIN1/GRIN2B-V618G. Glutamate displayed slightly increased potency in the R540H variant, but not in N615I and V618G variants. However, the inhibition by Mg(2+) was completely abolished in N615I and V618G variants. In fact, Mg(2+) enhanced glutamate responses in those variants. The potency of radiprodil to block glutamate-evoked currents was not affected in any of the variants, while the effects by non-selective NMDA inhibitors were greatly reduced in some of the variants. Additionally, in the Mg(2+) insensitive variants, radiprodil blocked glutamate-activated currents with the same potency as in the absence of Mg(2+). The gain of function observed in the reported GRIN2B variants could be a key pathophysiological factor leading to neuronal hyper-excitability in epileptic encephalopathies. The GluN2B-selective inhibitor radiprodil fully retained its pharmacological profile under these conditions, while other non-selective NMDA receptor antagonists lost their potency. Consequently, our data suggest that radiprodil may be a valuable therapeutic option for treatment of pediatric epileptic encephalopathies associated with GRIN2B mutations."}