Oxidation of Protein Tyrosine Phosphatases as a Pharmaceutical Mechanism of Action: A Study Using 4-Hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione

Liljebris, Charlotta; Baranczewski, Paweł; Björkstrand, Eva; Byström, Styrbjörn; Lundgren, Bo; Tjernberg, Agneta; Warolén, Malin; James, Sarah

doi:10.1124/jpet.103.062745

Cited by 22 publications

(27 citation statements)

References 28 publications

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“…The fact that NMDA was able to induce substance P release in a few rats suggested that there may be some factor that increases the functionality of these NMDA receptors. We previously found (Chen et al ., ) that addition of the protein tyrosine phosphatase (PTP) inhibitor BVT948 (Liljebris et al ., ) increased NMDA‐induced NK1R internalization, most probably by increasing tyrosine phosphorylation of the NR2B subunit of the NMDA receptor. Indeed, an intrathecal injection of BVT948 1 h before NMDA resulted in a significant increase in NMDA‐induced NK1R internalization (Fig.…”

Section: Resultsmentioning

confidence: 99%

BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals

Chen

Walwyn

Ennes

et al. 2014

Eur J of Neuroscience

101

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NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75NTR), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75NTR inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr1472 phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and an Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain.

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Section: Resultsmentioning

confidence: 99%

BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals

Chen

Walwyn

Ennes

et al. 2014

Eur J of Neuroscience

101

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“…If so, inhibiting PTPs should increase the tyrosine phosphorylation of the NMDA receptors and thus their ability to induce substance P release. Accordingly, we treated spinal cord slices with the PTP inhibitor BVT948 (10 µM) (Liljebris et al, 2004) before and during the addition of NMDA. We assumed that the increase in NMDA phosphorylation once PTPs were inhibited would proceed slowly, so we preincubated the slices with BVT948 fro 60 min, as in the case of PP1.…”

Section: Resultsmentioning

confidence: 99%

NMDA receptors in primary afferents require phosphorylation by Src family kinases to induce substance P release in the rat spinal cord

2010

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The function of NMDA receptors in primary afferents remains controversial, in particular regarding their ability to evoke substance P release in the spinal cord. The objective of this study was, first, to confirm that substance P release evoked by NMDA is mediated by NMDA receptors in primary afferent terminals. Second, we investigated whether these NMDA receptors are inactivated in some conditions, which would explain why their effect on substance P release was not observed in some studies. Substance P release was induced in spinal cord slices and measured as NK1 receptor internalization in lamina I neurons. NMDA (combined with D-serine) induced NK1 receptor internalization with an EC 50 of 258 nM. NMDA-induced NK1 receptor internalization was abolished by the NK1 receptor antagonist L-703,606, confirming that is was caused by substance P release, by NMDA receptor antagonists (MK1801 and ifenprodil), showing that it was mediated by NMDA receptors containing the NR2B subunit, and by preincubating the slices with capsaicin, showing that the substance P release was from primary afferents. However, it was not affected by lidocaine and ω-conotoxin MVIIA, which block Na + channels and voltage-dependent Ca 2+ channels, respectively. Therefore, NMDA-induced substance P release does not require firing of primary afferents or the opening of Ca 2+ channels, which is consistent with the idea that NMDA receptors induce substance P directly by letting Ca 2+ into primary afferent terminals. Importantly, NMDA-induced substance P release was eliminated by preincubating the slices for one hour with the Src family kinase inhibitors PP1 and dasatinib, and was substantially increased by the protein tyrosine phosphatase inhibitor BVT948. In contrast, PP1 did not affect NK1 receptor internalization induced by capsaicin. These results show that tyrosine-phosphorylation of these NMDA receptors is regulated by the opposite actions of Src family kinases and protein tyrosine phosphatases, and is required to induce substance P release. KeywordsC-fiber; dorsal horn; internalization; nociceptor; neurokinin-1 receptor; protein tyrosine phosphatase Corresponding author: Juan Carlos G. Marvizón, VA Greater Los Angeles Healthcare System, building 115, 11301 Wilshire Blvd., Los Angeles, CA 90073; phone: 310-478 3711 extension 41850; fax: 310-312 9289; marvizon@ucla.edu. * These authors contributed equally to the study and are listed in alphabetical order Section Editor: Linda S. Sorkin (Pain Mechanisms) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience....

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“…Such a possibility is not without precedent. We have previously reported the ability of a non-specific protein tyrosine phosphatase inhibitor to increase PI3K-dependent glucose transport in muscle cells in culture without being able to detect changes in basal tyrosine phosphorylation of the insulin receptor or IRS-1 [48]. Thus, it remains possible that HDAC inhibition by TSA leads to enhanced PKB phosphorylation through small changes in IRS-1 phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Untitled

Kaiser

James

2004

BMC Biol

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Background: Insulin receptor substrate (IRS) proteins are key moderators of insulin action. Their specific regulation determines downstream protein-protein interactions and confers specificity on growth factor signalling. Regulatory mechanisms that have been identified include phosphorylation of IRS proteins on tyrosine and serine residues and ubiquitination of lysine residues. This study investigated other potential molecular mechanisms of IRS-1 regulation.

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Oxidation of Protein Tyrosine Phosphatases as a Pharmaceutical Mechanism of Action: A Study Using 4-Hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione

Cited by 22 publications

References 28 publications

BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals

BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals

NMDA receptors in primary afferents require phosphorylation by Src family kinases to induce substance P release in the rat spinal cord

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