title: A genetically modified mouse model probing the selective action of ifenprodil at the N-methyl-D-aspartate type 2B receptor.
abstract: Selective antagonism of N-methyl-d-aspartate (NMDA) 2B subunit containing receptors has been suggested to have potential therapeutic application for multiple CNS disorders. The amino terminal NR2B residues 1 to 282 were found to be both necessary and sufficient for the binding and function of highly NR2B subunit specific antagonists like ifenprodil and CP-101,606. Using a genetic approach in mice, we successfully replaced the murine NR2B gene function by "knocking-in" (KI) a chimeric human NR2A/B cDNA containing the minimal domain abolishing ifenprodil binding into the endogenous NR2B locus. Patch-clamp recording from hippocampal cultures of the NR2B KI mice demonstrated that their NMDA receptors have reduced sensitivity to both ifenprodil and CP-101,606, as predicted, but also have a lower affinity for glycine. The NR2B KI mice exhibited normal locomotor activity making this ifenprodil-insensitive mouse model a valuable tool to test the specificity of NR2B selective antagonists in vivo.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. Thomas_Rosahl@merck.com
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rosahl
authors.forename: Peter B
authors.initials: PB
authors.lastname: Wingrove
authors.forename: Verity
authors.initials: V
authors.lastname: Hunt
authors.forename: Rosa L
authors.initials: RL
authors.lastname: Fradley
authors.forename: Jason M K
authors.initials: JM
authors.lastname: Lawrence
authors.forename: Robert P
authors.initials: RP
authors.lastname: Heavens
authors.forename: Patrick
authors.initials: P
authors.lastname: Treacey
authors.forename: Marcelo
authors.initials: M
authors.lastname: Usala
authors.forename: Alison
authors.initials: A
authors.lastname: Macaulay
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Bonnert
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Whiting
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010880:Piperidines; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C010739:ifenprodil