Control of Voltage-Independent Zinc Inhibition of NMDA Receptors by the NR1 Subunit

Traynelis, Stephen F.; Burgess, Michele; Zheng, Fang; Lyuboslavsky, Polina; Powers, Jennifer

doi:10.1523/jneurosci.18-16-06163.1998

Cited by 238 publications

(262 citation statements)

References 57 publications

(98 reference statements)

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“…Inhibitory effects of NAAG appear to be all-or-none. We do not know the reason for that, however, there is precedent for NMDAR inhibition where zinc has a steep dose-response curve of NR2A of approximately 80% (Paoletti et al, 1997;Traynelis et al, 1998).…”

Section: Discussionmentioning

confidence: 98%

NAAG Reduces NMDA Receptor Current in CA1 Hippocampal Pyramidal Neurons of Acute Slices and Dissociated Neurons

Bergeron¹,

Coyle

Tsai

et al. 2004

Neuropsychopharmacol

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N-Acetylaspartylglutamate (NAAG) is an abundant neuropeptide in the nervous system, yet its functions are not well understood. Pyramidal neurons of the CA1 sector of acutely prepared hippocampal slices were recorded using the whole-cell patch-clamp technique. At low concentrations (20 mM), NAAG reduced isolated N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic currents or NMDA-induced currents. The NAAG-induced change in the NMDA concentration/response curve suggested that the antagonism was not competitive. However, the NAAG-induced change in the concentration/response curve for the NMDAR co-agonist, glycine, indicated that glycine can overcome the NAAG antagonism. The antagonism of the NMDAR induced by NAAG was still observed in the presence of LY-341495, a potent and selective mGluR3 antagonist. Moreover, in dissociated pyramidal neurons of the CA1 region, NAAG also reduced the NMDA current and this effect was reversed by glycine. These results suggest that NAAG reduces the NMDA currents in hippocampal CA1 pyramidal neurons.

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Section: Discussionmentioning

confidence: 98%

NAAG Reduces NMDA Receptor Current in CA1 Hippocampal Pyramidal Neurons of Acute Slices and Dissociated Neurons

Bergeron¹,

Coyle

Tsai

et al. 2004

Neuropsychopharmacol

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show abstract

“…The quality and quantity of cRNA were assessed by gel electrophoresis. Preparation of oocytes and injection of cRNAs coding for wild-type and mutant NMDA receptors were performed as described (18).…”

Section: Methodsmentioning

confidence: 99%

“…Two electrode voltage-clamp recordings were made 2-7 days postinjection as described (18). Briefly, oocytes were perfused with a solution comprised of (in mM) 90 NaCl, 1 KCl, 10 Hepes, and 0.5 BaCl 2 at pH 7.3, and held under voltage clamp at Ϫ20 to Ϫ30 mV (or stated otherwise).…”

Section: Methodsmentioning

confidence: 99%

“…Our previous study (18) as well as more recent work (22) suggested that there may be structural and͞or functional links between inhibition of the NMDA receptor by extracellular protons and Zn 2ϩ . Here, we have explored the nature of the coupling between proton and Zn 2ϩ inhibition and show that there is a unique interaction between Zn 2ϩ and proton inhibition for NR2A-but not NR2B-containing receptors.…”

mentioning

confidence: 85%

“…It is well established that Zn 2ϩ can inhibit neuronal NMDA receptors through a dual mechanism involving both voltage-dependent channel block and a voltage-independent inhibition (11)(12)(13)(14). The voltage-independent Zn 2ϩ inhibition appears to be strongly dependent on subunit composition, being influenced by the NR2 subunits as well as NR1 splice variants in recombinant NMDA receptors (15)(16)(17)(18). Interestingly, recombinant receptors comprised of the NR2A subunit are much more sensitive to Zn 2ϩ than NR2B-, NR2C-, or NR2D-containing receptors, being inhibited in the nanomolar range by as much as 70% (15)(16)(17).…”

mentioning

confidence: 99%

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Molecular determinants of coordinated proton and zinc inhibition of N- methyl- d -aspartate NR1/NR2A receptors

Low

Zheng

Lyuboslavsky

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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157

206

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Modulation of the N-methyl-D-aspartate (NMDA)-selective glutamate receptors by extracellular protons and Zn 2؉ may play important roles during ischemia in the brain and during seizures. Recombinant NR1͞ NR2A receptors exhibit a much higher apparent affinity for voltageindependent Zn 2؉ inhibition than receptors with other subunit combinations. Here, we show that the mechanism of this apparent high-affinity, voltage-independent Zn 2؉ inhibition for NR2A-containing receptors results from the enhancement of proton inhibition. We also show that the N-terminal leucine͞isoleucine͞valine binding protein (LIVBP)-like domain of the NR2A subunit contains critical determinants of the apparent high-affinity, voltage-independent Zn 2؉ inhibition. Mutations H42A, H44G, or H128A greatly increase the Zn 2؉ IC50 (by up to Ϸ700-fold) with no effect on the potencies of glutamate and glycine or on voltage-dependent block by Mg 2؉ . Furthermore, the amino acid residue substitution H128A, which mediates the largest effect on the apparent high-affinity Zn 2؉ inhibition among all histidine substitutions we tested, is also critical to the pH-dependency of Zn 2؉ inhibition. Our data revealed a unique interaction between two important extracellular modulators of NMDA receptors.G lutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. Although overactivation of the N-methyl-D-aspartate (NMDA)-selective glutamate receptors can trigger neurodegeneration in neuropathological conditions such as stroke, NMDA receptor function is regulated under normal conditions by several extracellular ions (Mg 2ϩ , H ϩ , and Zn 2ϩ ), which exert strong tonic inhibition in a subunit selective manner (1). Inhibition by extracellular protons is particularly relevant for the neuropathological consequences of occlusive stroke because acidification of the extracellular environment during ischemia has been hypothesized to inhibit NMDA receptor overactivation by extrasynaptic glutamate that accumulates following metabolic failure (2, 3). The proton inhibition of NMDA receptors could delay their contribution to subsequent neuronal death until the pH gradients are restored, and this delay may provide a therapeutic window for postinsult treatment with NMDA receptor antagonists. Acidification of the extracellular space during electrographic seizure may also contribute to seizure termination through inhibition of NMDA receptor function (4, 5). Because of these potentially important aspects of the pH sensitivity of the NMDA receptor, we have sought to understand the structural basis by which the receptor might control its regulation by extracellular protons.In the central nervous system, the extracellular Zn 2ϩ concentration has been shown to vary under normal brain function as well as neuropathological conditions (6, 7). In addition, there are large amounts of chelatable Zn 2ϩ in the glutamatergic terminals of hippocampus (8-10), which are released in a Ca 2ϩ -dependent manner (for review, see ref. 6). ...

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Localization of alternatively spliced NMDAR1 glutamate receptor isoforms in rat striatal neurons

et al. 1999

J. Comp. Neurol.

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Control of Voltage-Independent Zinc Inhibition of NMDA Receptors by the NR1 Subunit

Cited by 238 publications

References 57 publications

NAAG Reduces NMDA Receptor Current in CA1 Hippocampal Pyramidal Neurons of Acute Slices and Dissociated Neurons

NAAG Reduces NMDA Receptor Current in CA1 Hippocampal Pyramidal Neurons of Acute Slices and Dissociated Neurons

Molecular determinants of coordinated proton and zinc inhibition of N- methyl- d -aspartate NR1/NR2A receptors

Localization of alternatively spliced NMDAR1 glutamate receptor isoforms in rat striatal neurons

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