The NR3B Subunit Does Not Alter the Anesthetic Sensitivities of Recombinant N-Methyl-d-Aspartate Receptors

Yamakura, Tomohiro; Askalany, Ahmed R.; Petrenko, Andrey B.; Kohno, Tatsuro; Baba, Hiroshi; Sakimura, Kenji

doi:10.1213/01.ane.0000152324.30272.49

Cited by 24 publications

(23 citation statements)

References 26 publications

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“…Increasing the amount of NR3B cDNA with respect to NR1 and NR2A correspondingly reduced the current amplitudes (Nishi et al, 2001). This is consistent with that reported in X. laevis oocyte expression system (Yamakura et al, 2005) that NR3 subunits exert a negative interfering effect in NMDA receptors Sucher et al, 1995;Das et al, 1998;Chatterton et al, 2002;Matsuda et al, 2002Matsuda et al, , 2003Yamakura et al, 2005).…”

Section: Nr1/nr3 Receptors Expressed In Oocytessupporting

confidence: 90%

“…The cotransfection of NR1, NR3A, and NR3B cDNAs into HEK293 cells produces triheteromeric NR1/NR3A/NR3B receptors yielding glycine-activated currents with novel functional and pharmacological properties (Pina-Crespo and Heinemann, 2004;Smothers and Woodward, 2007;Talantova et al, 2007). The glycine-activated currents of NR1/NR3A/ NR3B receptors resemble that observed in oocytes expressing NR1/NR3A (i.e., currents undergo rapid activation followed by rapid desensitization to steady-state levels) (Chatterton et al, 2002;Yamakura et al, 2005). The desensitization of activated NR1/NR3A/NR3B receptors is not affected by cyclothiazide.…”

Section: Nr1/nr3 Receptors Expressed In Oocytesmentioning

confidence: 73%

“…Thus, Zn 2ϩ can act as both a weak agonist and a potent positive modulator at NR1/NR3 receptors . Yamakura et al (2005) reported that NR3B subunit did not alter isoflurane and nitrous oxide sensitivities of NMDA receptors. Taken together, antagonists of or mutations within the glycine-binding site of the NR1 subunit produced large NR1/NR3 receptor currents, whereas mutations within the NR3 binding site resulted in a severe reduction of glycine currents (Awobuluyi et al, 2007).…”

Section: Nr1/nr3 Receptors Expressed In Oocytesmentioning

confidence: 97%

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New Insights into the Not-So-New NR3 Subunits of N-Methyl-d-aspartate Receptor: Localization, Structure, and Function

Low¹,

Wee²

2010

Mol Pharmacol

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The NR3 subunits (NR3A and NR3B) are new players in a well established field of N-methyl-D-aspartate (NMDA) receptors, previously involving the NR1 and NR2 subunits. Their incorporation into conventional NMDA receptors forms glutamate-activated NR1/NR2/NR3 triheteromers, whereas the omission of the glutamate-binding NR2 subunits results in excitatory glycine-activated NR1/NR3 diheteromers. These NR3-containing NMDA receptors exhibit several differences in receptor properties compared with the conventional NR1/NR2 receptors. This review highlights the major landmarks that have been achieved in the past decade or so involving NR3 subunit research in four key areas: the spatiotemporal mapping of NR3 protein, the structural elucidation of NR3 domains, pharmacological characterization of NR3-containing receptors, and the successful generation of NR3 knockout/transgenic animals. It is expected that further characterization of their functional roles coupled with the identification of endogenous and exogenous ligands will eventually advance the understanding of the basic pharmacology and the complex role of NMDA receptors in higher brain functions and neurological disorders.The N-methyl-D-aspartate (NMDA) receptor is a subtype of the ionotropic glutamate (iGlu) receptors, a family of ligand-gated ion channels that mediates the majority of excitatory neurotransmission in the mammalian central nervous system. Named after the agonist originally used to differentiate this receptor from two other iGlu receptor members [␣-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor and the 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine (kainate) receptor], the NMDA receptor is unlike the other subtypes in three important ways. First, it requires both L-glutamate (agonist) and glycine (coagonist) for maximum activation (Johnson and Ascher, 1987;Kleckner and Dingledine, 1988;Dalkara et al., 1992). Second, the unique presence of an Mg 2ϩ channel blockade brings about a voltage-dependence property absent in other iGlu receptor members (Mayer et al., 1984;Nowak et al., 1984;Kupper et al., 1998). Third, the NMDA receptor exhibits relatively higher permeability to calcium ion (Ca 2ϩ ) than AMPA and kainate receptors, which links it to a variety of neurophysiological processes including neurodevelopment and cognition, and neuropathological conditions such as bipolar disorder, Parkinson's disease, and stroke (Dingledine et al

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Section: Nr1/nr3 Receptors Expressed In Oocytessupporting

confidence: 90%

Section: Nr1/nr3 Receptors Expressed In Oocytesmentioning

confidence: 73%

Section: Nr1/nr3 Receptors Expressed In Oocytesmentioning

confidence: 97%

See 1 more Smart Citation

New Insights into the Not-So-New NR3 Subunits of N-Methyl-d-aspartate Receptor: Localization, Structure, and Function

Low¹,

Wee²

2010

Mol Pharmacol

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“…In contrast, another study showed that the sensitivities of NMDA receptors to Mg 2ϩ , isoflurane, ketamine, nitrous oxide, and ethanol were not altered by the NR3B subunit, although the NR3B subunit prominently reduced the amplitude of NMDA currents. 44 These results indicate that NMDA receptor-mediated synaptic transmission may not be affected by xenon in adult motoneurons. In any case, additional studies are required using identified spinal motoneurons in the adult rat.…”

Section: Discussionmentioning

confidence: 81%

Effect of Xenon on Excitatory and Inhibitory Transmission in Rat Spinal Ventral Horn Neurons

Yamamoto¹,

Honda²,

Baba

et al. 2012

Anesthesiology

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Background:The minimum alveolar concentration is determined in the spinal cord rather than in the brain. Xenon inhibits glutamatergic excitatory synaptic transmission in the dorsal horn neurons. However, its actions in the ventral horn neurons have not been investigated. Methods: The effects of 50 or 75% xenon on excitatory and inhibitory synaptic transmission were examined in the spinal lamina IX neurons of neonatal rats by using a whole cell patch clamp technique. Results: Fifty percent xenon inhibited the ␣-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid-induced currents (amplitudes ϭ 72 Ϯ 9% and integrated area ϭ 73 Ϯ 13% of the control values), and ␣-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid receptor-mediated electrically evoked excitatory postsynaptic currents (amplitudes ϭ 69 Ϯ 13% of the control values). Seventy-five percent xenon similarly inhibited ␣-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid-induced currents. However, xenon had no effect on the N-methyl-D-aspartate-induced currents or N-methyl-D-aspartate receptor-mediated electrically evoked excitatory postsynaptic currents. Xenon decreased the amplitude, but not the frequency, of miniature excitatory postsynaptic currents. There were no discernible effects on the currents induced by ␥-aminobutyric acid or glycine or on miniature inhibitory postsynaptic currents. Conclusions: Xenon inhibits ␣-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid receptor-mediated glutamatergic excitatory transmission in the spinal lamina IX neurons

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“…Ketamine blocks NMDA receptors through an interaction with sites thought to be located within the ion channel pore region (Orser et al, 1997). Recently, it was shown that inclusion of the NR3B subunit does not alter the ketamine sensitivity of recombinant NR1/NR2 receptors expressed in oo- jpet.aspetjournals.org cytes (Yamakura et al, 2005), Likewise, 100 M ketamine produced only weak inhibition (4.3 Ϯ 3.3% peak component and 7.9 Ϯ 6.8% steady-state component) of the glycineinduced current of NR1/NR3A/NR3B receptors (Fig. 9, B and C).…”

Section: Resultsmentioning

confidence: 99%

Pharmacological Characterization of Glycine-Activated Currents in HEK 293 Cells Expressing N-Methyl-D-aspartate NR1 and NR3 Subunits

Smothers

Woodward²

2007

J Pharmacol Exp Ther

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N-Methyl-D-aspartate (NMDA) receptors are important targets for drugs of abuse such as ethanol, toluene, and ketamine. Ligand-gated ion channels assembled from the NR1 and NR3 subunits have functional and pharmacological properties that are distinct from those of conventional NMDA receptors containing NR2 subunits. In the present study we used voltageclamp electrophysiology to characterize excitatory glycine-activated receptors assembled from NR1, NR3A, and NR3B subunits expressed in human embryonic kidney (HEK) 293 cells. These glycine-activated receptors were not stimulated by glutamate or kainic acid and were resistant to magnesium block. A wide variety of NMDA receptor antagonists including D-2-amino-5-phosphonovaleric acid, ifenprodil, memantine, (5R,10S)-(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) or acamprosate did not inhibit glycine-activated NR1/NR3A/NR3B receptors. Likewise, these receptors were not affected by antagonists of inhibitory glycine receptors or glycine transporters. The NMDA receptor glycine site agonist, D-serine, partially activated NR1/ NR3A/NR3B receptors, whereas the antagonist, 5,7-dichlorokynurenic acid, inhibited receptor currents. Conversely, the antagonist, 7-chlorokynurenic acid, and the partial agonist, R-(ϩ)-3-amino-1-hydroxy-2-pyrrolidinone (HA-966), potentiated glycine-stimulated currents of these receptors. NR1/ NR3A/NR3B receptor currents were inhibited by 10 to 21% by ethanol and toluene but were relatively insensitive to ketamine. Ethanol inhibition was enhanced in receptors expressing the NR1(L819A) mutant, whereas those containing NR1(F639A) or NR1(M813A) showed no change relative to the wild-type NR1. The results of this study indicate that coexpression of NR1, NR3A, and NR3B subunits in HEK 293 cells results in glycineactivated receptors with novel functional and pharmacological properties.N-Methyl-D-aspartate (NMDA) receptors are glutamateactivated ion channels that contain NR1 and NR2 subunits. A third class of NMDA receptor subunits has also been reported and consists of the NR3A and NR3B subunits (Ciabarra et al., 1995;Sun et al., 1998). NR3 subunits share structural features with the NR1 subunit, including the S1 and S2 agonist binding domains and some sequence similarity across transmembrane domains (Chatterton et al., 2002). Coexpression of the NR3A or NR3B subunits with NR1 and NR2 in recombinant expression systems decreases NMDA receptor current (Chatterton et al., 2002) and reduces calcium permeability (Matsuda et al., 2002). In NR3A-deficient mice, NMDA receptor currents are significantly enhanced (Das et al., 1998), suggesting that these subunits may be important modulators of NMDA receptor function.As for NR1 subunits, NR3 subunits do not form functional channels when expressed alone. However, coexpression of NR1 and NR3 subunits in oocytes has been reported to produce functional channels that are gated by glycine but not glutamate (Chatterton et al., 2002; but see Smothers and Woodward, 2003). In...

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The NR3B Subunit Does Not Alter the Anesthetic Sensitivities of Recombinant N-Methyl-d-Aspartate Receptors

Cited by 24 publications

References 26 publications

New Insights into the Not-So-New NR3 Subunits of N-Methyl-d-aspartate Receptor: Localization, Structure, and Function

New Insights into the Not-So-New NR3 Subunits of N-Methyl-d-aspartate Receptor: Localization, Structure, and Function

Effect of Xenon on Excitatory and Inhibitory Transmission in Rat Spinal Ventral Horn Neurons

Pharmacological Characterization of Glycine-Activated Currents in HEK 293 Cells Expressing N-Methyl-D-aspartate NR1 and NR3 Subunits

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