Src, a molecular switch governing gain control of synaptic transmission mediated by
            <i>N-</i>
            methyl-
            <scp>d</scp>
            -aspartate receptors

Yu, Xian‐Min; Salter, Michael W.

doi:10.1073/pnas.96.14.7697

Cited by 113 publications

(77 citation statements)

References 120 publications

(135 reference statements)

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“…Many NMDAR functions have been linked to tyrosine phosphorylation of the NR2 subunits. Phosphorylation results in the enhancement of channel function because tyrosine kinase inhibitors inhibit whereas application of Src kinase enhances NMDAR-mediated currents (Wang and Salter 1994;Chen and Leonard 1996;Yu and others 1997;Yu and Salter 1999). Both Fyn and Src have been implicated in playing an important role in LTP.…”

Section: Regulation Of Nmdar Function By Phosphorylation/dephosphorylmentioning

confidence: 99%

Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

Ron

2004

Neuroscientist

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One of the major targets for ethanol (alcohol) in the brain is the N-methyl-D-aspartate (NMDA) receptor, a glutamate-gated ion channel. Intriguingly, the effects of ethanol on the NMDA receptor are not homogeneous throughout the brain. This review focuses on recent studies revealing molecular mechanisms that mediate the actions of ethanol on the NMDA receptor in different brain regions via changes in NMDA receptor phosphorylation and compartmentalization. Specifically, the role of the scaffolding protein RACK1 and the regulatory protein DARPP-32 in mediating the distinct effects of ethanol is presented. KeywordsN-methyl-D-aspartate (NMDA); Ethanol; Phosphorylation; RACK1; Alcoholism is a devastating disease that affects 14 million people in the United States alone and costs society $165 billion a year. Alcoholism is defined as uncontrolled consumption of alcohol (ethanol) despite the negative consequences. The disease manifests itself or results from phenotypes such as tolerance, dependence, and withdrawal and/or craving. Considerable effort has been focused on elucidating the mechanisms that underlie the development and maintenance of alcohol addiction. Interestingly, although ethanol is a small diffusible molecule ( Fig. 1), only a defined number of targets have been identified that are altered as the result of acute or chronic exposure of neurons to ethanol (Fig. 1). Even more intriguing is the fact that ethanol affects the same targets differently in different brain regions. In this review, I will present examples of how signaling events that regulate the phosphorylation state and compartmentalization of proteins determine the activities of ethanol on the N-methyl-Daspartate (NMDA) receptor (NMDAR). Posttranslation Modification: Phosphorylation/DephosphorylationThe most common posttranslation modification is the addition of a phosphate group to the serine, threonine, or tyrosine residues of a protein substrate. This reaction, termed phosphorylation, is achieved via activation of protein kinases, which are divided into three groups: serine/threonine kinases, tyrosine kinases, and dual-specificity kinases, which are able to phosphorylate all three residues. The opposite reaction, in which a phosphate group is removed from a protein (dephosphorylation), is performed by either serine/threonine or tyrosine phosphatases. Receptor kinases and phosphatases are integral parts of the plasma membrane, whereas nonreceptor kinases and phosphatases reside intracellularly, with their subcellular compartmentalization determined in large part by protein-lipid or protein-protein interactions, as will be discussed in sections 3 and 6. Kinases and phosphatases are specifically Address correspondence to: Dorit Ron, Ernest Gallo Center, 5858 Horton St., Suite 200, Emeryville,.. NIH Public Access Author ManuscriptNeuroscientist. Author manuscript; available in PMC 2006 February 7. Published in final edited form as:Neuroscientist. 2004 August ; 10(4): 325-336. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ...

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Section: Regulation Of Nmdar Function By Phosphorylation/dephosphorylmentioning

confidence: 99%

Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

Ron

2004

Neuroscientist

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“…1c), neurons in which NMDARs are tonically upregulated by Src 14,21,22 . By contrast, administering a peptide with identical amino acid composition but with a scrambled sequence (sSrc40-49) had no effect on synaptic NMDAR currents.…”

Section: Constructing a Src-nmdar Uncoupling Peptide For Use In Vivomentioning

confidence: 99%

“…time and open probability upon binding of the co-agonists glutamate and glycine, leading to increased synaptic NMDARs currents 14 . Src is opposed by the phosphotyrosine phosphatase STEP 21 , and the balance of the activity between these two enzymes provides dynamic gain control of NMDAR function 16 .…”

Section: Within the Nmdar Complex Src Enhances Nmdar Function By Incmentioning

confidence: 99%

“…However, pharmacological blockade of these receptors in humans is deleterious because the activity of NMDARs is essential for many important physiological functions including breathing and locomotion 9,12,13 . A crucial signaling event for NMDAR-dependent neuroplasticity, including pain hypersensitivity 1,14 , is upregulation of NMDAR currents by mechanisms including relieving Mg 2+ blockade and receptor phosphorylation 15,16 . Thus, preferentially inhibiting mechanisms which upregulate NMDARs without affecting basal channel activity represents a strategy that may suppress pain hypersensitivity without impairing key physiological functions.…”

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confidence: 99%

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Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

Liu

Gingrich

Vargas‐Caballero

et al. 2008

Nat Med

199

205

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Chronic pain hypersensitivity depends upon N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects from suppressing physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund's adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses, or cardiovascular, respiratory, locomotor or cognitive functions. Thus, by targeting Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.Chronic pain is categorized as inflammatory or neuropathic, each involving neuroplastic changes leading to hypersensitivity in peripheral and central nociceptive systems 1,2 . Multiple mechanisms including increased primary afferent excitability 3 , enhanced transmission in the dorsal horn 1 , changes in gene expression 4 , aberrant neuron-glia interactions 5,6 and neuronal apoptosis 7 are implicated in hypersensitivity in chronic pain models. Abundant pre-clinical evidence indicates that N-methyl-D-aspartate receptor (NMDARs) 8 are critically involved in pain hypersensitivity 9-11 . However, pharmacological blockade of these receptors in humans is deleterious because the activity of NMDARs is essential for many important physiological functions including breathing and locomotion 9,12,13 . A crucial signaling event for NMDAR-dependent neuroplasticity, including pain hypersensitivity 1,14 , is upregulation of NMDAR currents by mechanisms including relieving Mg 2+ blockade and receptor phosphorylation 15,16 . Thus, preferentially inhibiting mechanisms which upregulate NMDARs without affecting basal channel activity represents a strategy that may suppress pain hypersensitivity without impairing key physiological functions.

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“…Finally, application of STEP postsynaptically prevented the induction of long-term potentiation by tetanic stimulation in the CA1 region of hippocampal neurons (17). Thus, STEP ap-pears to counter the activity of Src family members known to up-regulate synaptic transmission at excitatory synapses (18). The exact mechanisms by which this occurs remain unclear.…”

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confidence: 99%

Striatal Enriched Phosphatase 61 Dephosphorylates Fyn at Phosphotyrosine 420

Nguyen

Liu

Lombroso

2002

Journal of Biological Chemistry

171

189

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A family of protein tyrosine phosphatases enriched within the central nervous system called striatal enriched phosphatase (STEP) has been implicated in the regulation of the N-methyl-D-aspartate receptor. STEP 61 , a membrane-associated isoform located in the postsynaptic densities (PSDs) of striatal neurons, contains two transmembrane domains, two proline-rich domains, and a kinase-interacting motif. This study demonstrates that STEP 61 Dynamic regulation of protein tyrosine phosphorylation requires a balance between the activity of protein tyrosine kinases and protein tyrosine phosphatases (PTPs).1 One of the best-characterized families of protein tyrosine kinases is the Src kinase family, which consists of several members including Src, Fyn, Lyn, Lck, and Yes. These proteins are highly conserved in their amino acid sequences and their regulatory domains. Each member also contains a unique domain at the N terminus that distinguishes it from other family members (see review, Ref. 1).Src and Fyn are present within postsynaptic densities of central nervous system neurons (2, 3). Their presence at the PSD and their direct association with both receptors and key anchoring proteins such as PSD-95 (4) suggest that they regulate signaling events within these neurons. Indeed, several recent studies show that members of the Src kinase family modulate synaptic transmission by regulating the level of tyrosine phosphorylation of proteins within the PSD including the NR2 subunit of the N-methyl-D-aspartate (NMDA) receptor (5, 6).The Src family kinases are themselves regulated by tyrosine phosphorylation. They contain two conserved tyrosine residues that are phosphorylated (tyrosine 420 and tyrosine 531; numbering according to the amino acid sequence of human Fyn). Phosphorylation of tyrosine 531 of Fyn by C-terminal Src kinase leads to its inactivation (7,8). Dephosphorylation of this site results in a conformational change and activation of the protein through autophosphorylation at the second site, Tyr 420 . The dynamic balance in the level of phosphorylation at these two sites contributes to the overall level of Fyn kinase activity.

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Src, a molecular switch governing gain control of synaptic transmission mediated by N- methyl- d -aspartate receptors

Cited by 113 publications

References 120 publications

Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

Striatal Enriched Phosphatase 61 Dephosphorylates Fyn at Phosphotyrosine 420

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