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J Physiol
2012 Aug 15;59016:3857-75. doi: 10.1113/jphysiol.2012.234062.
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GluN1 splice variant control of GluN1/GluN2D NMDA receptors.
Vance KM
,
Hansen KB
,
Traynelis SF
.
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NMDA receptors are ionotropic glutamate receptors that mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the central nervous system. Recombinant GluN1-1a/GluN2D receptors are characterized by low channel open probability and prolonged deactivation time course following the removal of agonist. Here, we show that the deactivation time course, agonist potency, and single channel properties of GluN2D-containing NMDA receptors are modulated by alternative RNA splicing of GluN1. Our results demonstrate that GluN1 exon 5, which encodes a 21-amino-acid insert in the amino-terminal domain, is a key determinant of GluN1/GluN2D receptor function. GluN1-1b/GluN2D receptors, which contain the residues encoded by exon 5, deactivate with a dual exponential time course described by a τFAST of 410 ms and a τSLOW of 1100 ms. This time course is 3-fold more rapid than that for exon 5-lacking GluN1-1a/GluN2D, which deactivates with a τFAST of 1100 ms and a τSLOW of 3400 ms. Exon 5-containing NMDA receptors also have a two-fold higher open probability (0.037) than exon 5-lacking receptors (0.017). Furthermore, inclusion of exon 5-encoded residues within the GluN1-1b subunit decreases the potency for the endogenous agonist l-glutamate. Evaluation of receptor kinetics for NMDA receptors containing mutated GluN1-1b subunits and wild-type GluN2D identified residue Lys211 in GluN1-1b as a key determinant of exon 5 control of the deactivation time course and glutamate potency. Evaluation of a kinetic model of GluN1/GluN2D gating suggests that residues encoded by exon 5 influence several rate-limiting steps. These data demonstrate that the GluN1 subunit is a key determinant of the kinetic and pharmacological properties of GluN2D-containing NMDA receptors.
Acker,
Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators.
2011, Pubmed
Acker,
Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators.
2011,
Pubmed
Amico-Ruvio,
Stationary gating of GluN1/GluN2B receptors in intact membrane patches.
2010,
Pubmed
Auerbach,
Gating reaction mechanisms for NMDA receptor channels.
2005,
Pubmed
,
Xenbase
Banke,
Activation of NR1/NR2B NMDA receptors.
2003,
Pubmed
Banke,
Protons trap NR1/NR2B NMDA receptors in a nonconducting state.
2005,
Pubmed
Brickley,
NR2B and NR2D subunits coassemble in cerebellar Golgi cells to form a distinct NMDA receptor subtype restricted to extrasynaptic sites.
2003,
Pubmed
Brothwell,
NR2B- and NR2D-containing synaptic NMDA receptors in developing rat substantia nigra pars compacta dopaminergic neurones.
2008,
Pubmed
Chen,
Influence of a threonine residue in the S2 ligand binding domain in determining agonist potency and deactivation rate of recombinant NR1a/NR2D NMDA receptors.
2004,
Pubmed
,
Xenbase
Christopoulos,
Assessing the distribution of parameters in models of ligand-receptor interaction: to log or not to log.
1998,
Pubmed
Clarke,
NMDA receptor NR2 subunit dependence of the slow component of magnesium unblock.
2006,
Pubmed
Colquhoun,
A note on correlations in single ion channel records.
1987,
Pubmed
Colquhoun,
Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate.
1985,
Pubmed
Cull-Candy,
Role of distinct NMDA receptor subtypes at central synapses.
2004,
Pubmed
Dravid,
Activation of recombinant NR1/NR2C NMDA receptors.
2008,
Pubmed
Ehlers,
Regulated subcellular distribution of the NR1 subunit of the NMDA receptor.
1995,
Pubmed
Ehlers,
Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit.
1996,
Pubmed
Ehlers,
Splice variant-specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments.
1998,
Pubmed
Erreger,
Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles.
2005,
Pubmed
Forsythe,
Slow excitatory postsynaptic currents mediated by N-methyl-D-aspartate receptors on cultured mouse central neurones.
1988,
Pubmed
Gielen,
Mechanism of differential control of NMDA receptor activity by NR2 subunits.
2009,
Pubmed
Harney,
Extrasynaptic NR2D-containing NMDARs are recruited to the synapse during LTP of NMDAR-EPSCs.
2008,
Pubmed
Hollmann,
Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor.
1993,
Pubmed
,
Xenbase
Horak,
Different roles of C-terminal cassettes in the trafficking of full-length NR1 subunits to the cell surface.
2009,
Pubmed
Jackson,
Successive openings of the same acetylcholine receptor channel are correlated in open time.
1983,
Pubmed
Jones,
Functional NR2B- and NR2D-containing NMDA receptor channels in rat substantia nigra dopaminergic neurones.
2005,
Pubmed
Karakas,
Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors.
2011,
Pubmed
,
Xenbase
Kornau,
Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95.
1995,
Pubmed
Kuner,
Multiple structural elements determine subunit specificity of Mg2+ block in NMDA receptor channels.
1996,
Pubmed
,
Xenbase
Kuo,
Na+ channels must deactivate to recover from inactivation.
1994,
Pubmed
Laurie,
Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA.
1994,
Pubmed
Lester,
Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents.
1990,
Pubmed
Lin,
Postsynaptic density protein-95 regulates NMDA channel gating and surface expression.
2004,
Pubmed
,
Xenbase
Misra,
Identification of subunits contributing to synaptic and extrasynaptic NMDA receptors in Golgi cells of the rat cerebellum.
2000,
Pubmed
Misra,
Slow deactivation kinetics of NMDA receptors containing NR1 and NR2D subunits in rat cerebellar Purkinje cells.
2000,
Pubmed
Momiyama,
Distinct synaptic and extrasynaptic NMDA receptors identified in dorsal horn neurones of the adult rat spinal cord.
2000,
Pubmed
Momiyama,
Identification of a native low-conductance NMDA channel with reduced sensitivity to Mg2+ in rat central neurones.
1996,
Pubmed
Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed
Mullasseril,
A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors.
2010,
Pubmed
Pabba,
The elusive roles of NMDA receptor amino-terminal domains.
2012,
Pubmed
Popescu,
Modal gating of NMDA receptors and the shape of their synaptic response.
2003,
Pubmed
Pérez-Otaño,
Homeostatic plasticity and NMDA receptor trafficking.
2005,
Pubmed
Qian,
NR2 subunit-dependence of NMDA receptor channel block by external Mg2+.
2005,
Pubmed
Qin,
Maximum likelihood estimation of aggregated Markov processes.
1997,
Pubmed
Rauner,
Triheteromeric NR1/NR2A/NR2B receptors constitute the major N-methyl-D-aspartate receptor population in adult hippocampal synapses.
2011,
Pubmed
Renzi,
Climbing-fibre activation of NMDA receptors in Purkinje cells of adult mice.
2007,
Pubmed
Rumbaugh,
Exon 5 and spermine regulate deactivation of NMDA receptor subtypes.
2000,
Pubmed
Rutter,
Further characterization of the molecular interaction between PSD-95 and NMDA receptors: the effect of the NR1 splice variant and evidence for modulation of channel gating.
2002,
Pubmed
Schorge,
Maximum likelihood fitting of single channel NMDA activity with a mechanism composed of independent dimers of subunits.
2005,
Pubmed
,
Xenbase
Siegler Retchless,
A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction.
2012,
Pubmed
Sobolevsky,
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
2009,
Pubmed
Standaert,
Alternatively spliced isoforms of the NMDAR1 glutamate receptor subunit: differential expression in the basal ganglia of the rat.
1993,
Pubmed
Standaert,
Organization of N-methyl-D-aspartate glutamate receptor gene expression in the basal ganglia of the rat.
1994,
Pubmed
Talukder,
GluN1-specific redox effects on the kinetic mechanism of NMDA receptor activation.
2011,
Pubmed
,
Xenbase
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Traynelis,
Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines.
1995,
Pubmed
,
Xenbase
Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase
Vance,
Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors.
2011,
Pubmed
Vicini,
Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors.
1998,
Pubmed
Wyllie,
Single-channel currents from recombinant NMDA NR1a/NR2D receptors expressed in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Wyllie,
Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors.
1998,
Pubmed
,
Xenbase
Yuan,
Control of NMDA receptor function by the NR2 subunit amino-terminal domain.
2009,
Pubmed
,
Xenbase
Zhang,
The relationship between agonist potency and AMPA receptor kinetics.
2006,
Pubmed
Zhang,
Distinct gating modes determine the biphasic relaxation of NMDA receptor currents.
2008,
Pubmed
Zukin,
Alternatively spliced isoforms of the NMDARI receptor subunit.
1995,
Pubmed
