Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition

Zheng, Fang; Gingrich, Melissa B.; Traynelis, Stephen F.; Conn, P. Jeffrey

doi:10.1038/634

Cited by 170 publications

(165 citation statements)

References 37 publications

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“…Furthermore, injection of purified wild-type Pyk2 increases NMDA receptor currents, and this effect is blocked by inhibition of Src. In contrast, the Src-mediated increase in NMDA receptor activity (31)(32)(33) is not antagonized by dominant negative Pyk2 (49). These results place PKC upstream of Pyk2 and Src downstream of Pyk2 in that signaling pathway (49).…”

Section: Discussionmentioning

confidence: 51%

Interaction of the Tyrosine Kinase Pyk2 with the N-Methyl-d-aspartate Receptor Complex via the Src Homology 3 Domains of PSD-95 and SAP102

Seabold

Burette

Lim

et al. 2003

Journal of Biological Chemistry

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At low stimulus frequency, synaptic transmission depends largely upon ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) 1 -type glutamate receptors (1, 2). High frequency stimulation promotes Ca 2ϩ influx through N-methyl-D-aspartate (NMDA) receptors, thereby inducing long term potentiation (LTP) (1,3,4). LTP is a lasting increase in synaptic transmission that may underlie learning and memory (5, 6). NMDA receptors likely consist of one or two NR1 and two or three NR2 subunits; each subunit has an extracellular N terminus and an intracellular C terminus (7-10). The very C termini of NR2 subunits interact with the first two PDZ domains of PSD-95/SAP90 and the related proteins SAP102 and PSD-93/chapsyn110. PSD-95 and its homologs (SAP102, PSD-93, and SAP97) are scaffolding proteins consisting of three PDZ domains, one SH3 domain, and one GK domain. PSD-95, PSD-93, and SAP102 are thought to be involved in clustering glutamate receptors together with other proteins at postsynaptic sites (11-15). SAP97 interacts with the AMPA receptor subunit GluR1 (16 -18). SAP97 colocalizes with GluR1, but not GluR2/3, at postsynaptic sites (17). This interaction may already occur early in the secretory pathway and may be involved in trafficking or targeting of AMPA receptors (19).SH3 and GK domains of PSD-95 and its homologs form intramolecular and, to some degree, intermolecular interactions (20 -24). A point mutation in the Drosophila protein Dlg (a homolog of PSD-95) results in the substitution of a conserved leucine in the SH3 domain to a proline; this mutation leads to the loss of septate junction formation and overproliferation of the imaginal disc (25). Replacing the homologous leucine (Leu-460) with a proline in the SH3 domain of PSD-95 inhibits the interaction of the mutant SH3 domain with the GK domain (20,22). Collectively these findings indicate the physiological importance of the SH3-GK domain interaction, but a molecular function of this interaction remains to be established.Tyrosine phosphorylation of NR2B (26, 27) is augmented on LTP induction (28, 29), and several observations suggest that up-regulation of NMDA receptor activity by Src-mediated tyrosine phosphorylation is an important step in the induction of LTP. 1) Src increases NMDA receptor activity (30 -32) by elevating its peak current (33), 2) the activity of Src is up-regulated during LTP (34), 3) inhibition of Src can prevent LTP (30), and 4) an increase in synaptic transmission on Src activation occludes subsequent LTP induction (34).It is well established that Src can be activated by another tyrosine kinase, Pyk2/CAK␤/CADTK (35-38). Pyk2 is stimulated upon Ca 2ϩ influx, activation of PKC by phorbol esters, or stimulation of G q -linked receptors such as the muscarinic acetylcholine receptor M1 or the metabotropic glutamate receptor mGluR1 (35, 37, 39 -48). Neither Ca 2ϩ nor PKC appear to directly regulate Pyk2 in vitro (39); how Ca 2ϩ or PKC activates Pyk2 in vivo is unknown. When stimulated, Pyk2 autophosphorylates itself on tyrosine 402. The...

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Section: Discussionmentioning

confidence: 51%

Interaction of the Tyrosine Kinase Pyk2 with the N-Methyl-d-aspartate Receptor Complex via the Src Homology 3 Domains of PSD-95 and SAP102

Seabold

Burette

Lim

et al. 2003

Journal of Biological Chemistry

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“…EDTA (pH 7.3, 1-10 M) was added to control solutions containing saturating concentrations of glutamate (20-50 M) or NMDA (200 M) and glycine (10-100 M) to chelate the contaminant Zn 2ϩ . The ambient Zn 2ϩ concentration (17) in our solution was Ϸ300 nM (25) and arised predominantly as a contaminant from the NaCl. Tricine was used to buffer Zn 2ϩ concentrations 0.003-3 M (as described above) and ADA [N-2-acetamidoiminodiacetic acid (Sigma); log stability constants K 1 ϭ 7.1 and K 2 ϭ 9.22] (1 mM) was used to buffer Zn 2ϩ concentrations 0.1-100 nM (28) for experiments with NR2A-containing NMDA receptors.…”

Section: Methodsmentioning

confidence: 99%

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.

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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“…In the majority of cortical neurons, however, addition of Zn 2ϩ below 30 M had no detectable effect (n ϭ 12; data not shown), indicating the lack of high-affinity Zn 2ϩ modulation of ASICs. Previous studies, however, have reported that most physiological solutions contain contaminating concentrations of Zn 2ϩ in the range of 20 -50 nM (Paoletti et al, 1997;Amar et al, 2001) or higher (Zheng et al, 1998;Wilkins and Smart, 2002). The lack of effect by low micromolar Zn 2ϩ may also suggest that a high-affinity Zn 2ϩ binding site or sites, if any, have already been saturated by contaminating Zn 2ϩ in the extracellular solutions.…”

Section: Chelation Of Contaminating Znmentioning

confidence: 99%

Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels

et al. 2004

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Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition

Cited by 170 publications

References 37 publications

Interaction of the Tyrosine Kinase Pyk2 with the N-Methyl-d-aspartate Receptor Complex via the Src Homology 3 Domains of PSD-95 and SAP102

Interaction of the Tyrosine Kinase Pyk2 with the N-Methyl-d-aspartate Receptor Complex via the Src Homology 3 Domains of PSD-95 and SAP102

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

Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels

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