Tyrosine Phosphatase STEP Is a Tonic Brake on Induction of Long-Term Potentiation

Pelkey, Kenneth A.; Askalan, Rand; Paul, Surojit; Kalia, Lorraine V.; Nguyen, Tri Hung; Pitcher, Graham; Salter, Michael W.; Lombroso, Paul J.

doi:10.1016/s0896-6273(02)00633-5

Cited by 191 publications

(245 citation statements)

References 40 publications

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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%

“…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 . Our findings indicate that peripheral inflammation causes a rapid onset and sustained Src-dependent increase in tyrosine phosphorylation, which may enhance the function of NMDARs in the spinal cord.…”

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

confidence: 99%

“…For co-immunoprecipitation NMDAR and its associated proteins, crude synaptosomal fraction from forebrain or spinal cord was prepared as described previously 21 . For in vitro competition experiments, Src40-49Tat or Scrambled Src40-49Tat,(10μM), was incubated with the lysate 30 min before adding antibody for immunoprecipitation.…”

Section: Co-immunoprecipitation Immunoprecipitation and Immunoblottingmentioning

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

confidence: 99%

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

confidence: 99%

Section: Co-immunoprecipitation Immunoprecipitation and Immunoblottingmentioning

confidence: 99%

See 1 more Smart Citation

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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“…These include two transmembrane domains, two polyproline domains, and two PEST sequences. Electron microscopy and biochemical analyses have localized STEP 61 to the endoplasmic reticulum and postsynaptic terminal, where it is associated both with the postsynaptic density (Bult et al, 1996;Boulanger et al, 1995;Oyama et al, 1995) and the N-methyl-D-aspartate (NMDA) receptor protein complex (Pelkey et al, 2002). STEP-family proteins contain an ERK binding domain, the kinase interacting motif (KIM), which is required for the association of STEP with the ERKs (Paul et al, 2003;Pulido et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

The Striatal-Enriched Protein Tyrosine Phosphatase Gates Long-Term Potentiation and Fear Memory in the Lateral Amygdala

Paul

Olausson

Venkitaramani

et al. 2007

Biological Psychiatry

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“…In studies of schizophrenic individuals, NRG1 expression is increased in both the cortex 30 and hippocampus 31 , where NRG1-ErbB4 signaling is excessive 12,31 . As NRG1β blocks NMDAR-dependent long-term potentiation (LTP) at hip-pocampal Schaffer collateral-CA1 synapses [32][33][34][35][36][37] , a form of LTP also dependent on Src activity 5,38,39 , we determined the effect of NRG1β-ErbB4 signaling on Src-mediated enhancement of NMDAR function, tyrosine phosphorylation of NMDARs and the resultant potentiation of synaptic transmission. We examined neuronal responses not only in the hippocampus but also in the prefrontal cortex (PFC); both of these brain regions are crucial in the pathobiology of cognitive dysfunction in schizophrenia 21,[40][41][42][43] .…”

mentioning

confidence: 99%

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Pitcher

Kalia

et al. 2011

Nat Med

153

146

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Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.Correspondence should be addressed to M.W.S. (mike.salter@utoronto.ca). 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Medicine website. AUTHOR CONTRIBUTIONSG.M.P. designed the project, conducted the hippocampal experiments, analyzed the data and wrote the manuscript. L.V.K. and D.N. carried out and analyzed biochemical experiments. E.K.L. oversaw and analyzed the prefrontal cortex experiments. N.M.G. carried out and analyzed the prefrontal cortex experiments. K.T.Y. maintained, housed and provided ErbB4 knockout mice. All authors participated in revising the manuscript and agreed to the final version. M.W.S. conceived the study, analyzed data, supervised the overall project and wrote the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. Nat Med. Author manuscript; available in PMC 2012 January 23. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptThe NMDAR, a major excitatory ligand-gated ion channel in the central nervous system and a principal mediator of synaptic plasticity, is a multiprotein complex whose core is a heterotetramer comprising two obligate GluN1 subunits and two GluN2(A-D) subunits 1,2 . Proteins associated with the core NMDAR have key roles in trafficking, stability, subunit composition and function of NMDARs 3 . A key process regulating NMDAR activity is phosphorylation by NMDAR-associated kinases. Certain NMDAR-dependent functions, such as ventilation and locomotion, may be independent of NMDAR phosphorylation 4 , whereas phosphorylation-induced upregulation of NMDARs is critical for synaptic plasticity [5][6][7] .A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as...

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Tyrosine Phosphatase STEP Is a Tonic Brake on Induction of Long-Term Potentiation

Cited by 191 publications

References 40 publications

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

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

The Striatal-Enriched Protein Tyrosine Phosphatase Gates Long-Term Potentiation and Fear Memory in the Lateral Amygdala

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

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