title: Subtype-dependent N-methyl-D-aspartate receptor amino-terminal domain conformations and modulation by spermine.
abstract: The N-methyl-d-aspartate (NMDA) subtype of the ionotropic glutamate receptors is the primary mediator of calcium-permeable excitatory neurotransmission in the central nervous system. Subunit composition and binding of allosteric modulators to the amino-terminal domain determine the open probability of the channel. By using luminescence resonance energy transfer with functional receptors expressed in CHO cells, we show that the cleft of the amino-terminal domain of the GluN2B subunit, which has a lower channel open probability, is on average more closed than the GluN2A subunit, which has a higher open probability. Furthermore, the GluN1 amino-terminal domain adopts a more open conformation when coassembled with GluN2A than with GluN2B. Binding of spermine, an allosteric potentiator, opens the amino-terminal domain cleft of both the GluN2B subunit and the adjacent GluN1 subunit. These studies provide direct structural evidence that the inherent conformations of the amino-terminal domains vary based on the subunit and match the reported open probabilities for the receptor.
authors.affiliation: From the Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas 77030.
authors.forename: Rita E
authors.initials: RE
authors.lastname: Sirrieh
authors.affiliation: From the Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas 77030.
authors.forename: David M
authors.initials: DM
authors.lastname: MacLean
authors.affiliation: From the Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas 77030 vasanthi.jayaraman@uth.tmc.edu.
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Jayaraman
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013096:Spermine / Q000494:pharmacology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor
keywords: conformational change; fluorescence; fluorescence resonance energy transfer (FRET); glutamate receptor; ligand-binding protein
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