INT89845

Context Info Confidence 0.44 First Reported 2000 Last Reported 2010 Negated 0 Speculated 1 Reported most in Body Documents 19 Total Number 22 Disease Relevance 7.50 Pain Relevance 9.01

mitochondrion (Src) enzyme binding (Src) response to stress (Src) cytoplasm (Src) cytosol (Src) cell proliferation (Src)

Anatomy Link Frequency neurons 4 spinal cord 2 dorsal horns 2 brain 1 epithelial cell 1 Src (Rattus norvegicus)

Pain Link Frequency Relevance Heat Spinal cord 195 100.00 Delta opioid receptors 2 100.00 MU agonist 1 99.72 opioid receptor 13 99.60 nMDA receptor 330 99.42 Lasting pain 42 99.30 intrathecal 99 99.16 long-term potentiation 31 98.88 cINOD 14 97.74 Dorsal horn neuron 38 97.64

Disease Link Frequency Relevance Heat Stress 4 100.00 Systemic Sclerosis 90 99.66 Adhesions 4 99.56 Vasculitis 9 99.46 Pain 104 99.30 Wound Healing 2 93.48 INFLAMMATION 61 93.00 Ulcers 4 92.36 Fibrosis 12 91.12 Hyperalgesia 150 90.12

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

Over the past decade, a large body of evidence has accumulated showing that a main function of Src is to upregulate the activity of N-methyl-D-aspartate (NMDA) receptors and other ion channels.

Positive_regulation (upregulate) of Src in body

1) Confidence 0.44 Published 2004 Journal Oncogene Section Abstract Doc Link 15489918 Disease Relevance 0 Pain Relevance 0.27

The NMDA receptor currents must be further enhanced during the high frequency stimulation by the calcium-dependent activation of Pyk2 and Src kinases in order to induce LTP [5].

Positive_regulation (activation) of Src associated with nmda receptor and long-term potentiation

2) Confidence 0.39 Published 2008 Journal Mol Brain Section Body Doc Link PMC2651131 Disease Relevance 0.15 Pain Relevance 0.59

Finally, even though SRC represents an acute form of renal involvement, vascular pathology may be observed in SSc patients in the absence of SRC.

Positive_regulation (absence) of SRC associated with systemic sclerosis

3) Confidence 0.36 Published 2010 Journal International Journal of Rheumatology Section Body Doc Link PMC2958499 Disease Relevance 1.17 Pain Relevance 0.09

Our findings (Battaglia et al., 2003, and present work) support the idea of an activation by ephrinB2 of postsynaptic EphB receptors in neurons of the dorsal horn, since we showed that EphB1 receptors are present in dorsal horn neurons, where they are found in close association with NMDA receptors, and intrathecal administration of ephrinB2-Fc induces an increase in phosphorylated Src kinase associated with the EphB receptor itself.

Positive_regulation (increase) of Src in neurons associated with nmda receptor, dorsal horn, dorsal horn neuron and intrathecal

4) Confidence 0.33 Published 2008 Journal Neuroscience Section Body Doc Link PMC2568875 Disease Relevance 1.01 Pain Relevance 0.93

We therefore formulated the hypothesis that EphB receptors are involved in synaptic plasticity in vivo in the spinal cord (underlying chronic pain states) via a mechanism involving Src activation and NR2B phosphorylation.

Positive_regulation (activation) of Src in spinal cord associated with lasting pain and spinal cord

5) Confidence 0.33 Published 2008 Journal Neuroscience Section Body Doc Link PMC2568875 Disease Relevance 0.47 Pain Relevance 0.76

The mechanism apparently involved Src family kinases, since the level of phospho-Src bound to EphB receptors in the dorsal horns of the spinal cord was increased.

Positive_regulation (increased) of phospho-Src in dorsal horns associated with spinal cord

6) Confidence 0.33 Published 2008 Journal Neuroscience Section Body Doc Link PMC2568875 Disease Relevance 0.68 Pain Relevance 1.12

Interestingly, they also found that, in the absence of SRC, a significant increase in arterial fibrointimal thickness was observed in dcSSc patients, and to a lesser extent in lcSSc patients, compared to controls.

Positive_regulation (increase) of SRC

7) Confidence 0.33 Published 2010 Journal International Journal of Rheumatology Section Body Doc Link PMC2958499 Disease Relevance 0.80 Pain Relevance 0.07

In the present study, we investigated whether Src activity contributed to this sorting pattern and to functional desensitization of DORs.

Spec (whether) Positive_regulation (contributed) of Src

8) Confidence 0.33 Published 2009 Journal J. Cell. Mol. Med. Section Abstract Doc Link 18363847 Disease Relevance 0 Pain Relevance 0.62

Such vascular changes may be due to the presence of mild ongoing renal vascular injury below the threshold which triggers SRC. 5.

Positive_regulation (triggers) of SRC associated with vasculitis

9) Confidence 0.31 Published 2010 Journal International Journal of Rheumatology Section Body Doc Link PMC2958499 Disease Relevance 0.67 Pain Relevance 0.06

The identification of Abl as a downstream target in hippocampal neurons coupled with the requirement of Src to fully activate Abl after PDGF receptor activation may help reconcile the apparent contradiction in the requirement of Src for an inhibition of NMDA receptor currents by PDGF receptor activation and the direct potentiation of NMDA receptors by Src [14].

Positive_regulation (requirement) of Src in neurons associated with nmda receptor

10) Confidence 0.28 Published 2008 Journal Mol Brain Section Body Doc Link PMC2651131 Disease Relevance 0 Pain Relevance 0.22

Activation of Src kinase via the phosphorylation of tyrosine 416 is associated with a potentiation of NMDA receptor currents and an increase in long-term potentiation [40-42].

Positive_regulation (Activation) of Src associated with nmda receptor and long-term potentiation

11) Confidence 0.28 Published 2008 Journal Mol Brain Section Body Doc Link PMC2651131 Disease Relevance 0 Pain Relevance 0.12

The identification of Abl as a downstream target in hippocampal neurons coupled with the requirement of Src to fully activate Abl after PDGF receptor activation may help reconcile the apparent contradiction in the requirement of Src for an inhibition of NMDA receptor currents by PDGF receptor activation and the direct potentiation of NMDA receptors by Src [14].

Positive_regulation (requirement) of Src in neurons associated with nmda receptor

12) Confidence 0.28 Published 2008 Journal Mol Brain Section Body Doc Link PMC2651131 Disease Relevance 0 Pain Relevance 0.21

Interestingly, PDGF-BB treatment increased the phosphorylation of Src at both tyrosine 416 (tyrosine phosphorylation here potentiates Src activity) and 527 (tyrosine phosphorylation inhibits Src activity) [39].

Positive_regulation (potentiates) of Src

13) Confidence 0.28 Published 2008 Journal Mol Brain Section Body Doc Link PMC2651131 Disease Relevance 0 Pain Relevance 0.11

Indeed, EphB2 activation of Src by phosphorylation in cultured hippocampal and cortical neurons could induce NR2A phosphorylation (Grunwald et al., 2001).

Positive_regulation (activation) of Src in neurons

14) Confidence 0.24 Published 2008 Journal Neuroscience Section Body Doc Link PMC2568875 Disease Relevance 0.14 Pain Relevance 0.30

Interestingly, Takasu et al. (2002) showed that in primary cortical neurons in culture EphB activation by ephrinB2-Fc (immunoglobulin Fc fusion protein of ephrinB2) induced Src-dependent NR2B phosphorylation and furthermore we showed that intrathecal injection of ephrinB2-Fc induces Src phosphorylation in the spinal cord of adult rats (Battaglia et al., 2003).

Positive_regulation (induced) of Src in spinal cord associated with spinal cord and intrathecal

15) Confidence 0.24 Published 2008 Journal Neuroscience Section Body Doc Link PMC2568875 Disease Relevance 0.32 Pain Relevance 0.57

We did not reprobe for amounts of total Src/Fyn/Yes as total levels of those proteins bound to NR2B are directly affected by phosphorylation, i.e. phosphorylation promotes the association of the proteins to NR2B (Yu et al., 1997); the ratio of phospho-Src/total Src could thus potentially remain constant despite a significant increase in the total amount of activated phospho-Src bound to NR2B.

Positive_regulation (increase) of phospho-Src

16) Confidence 0.22 Published 2008 Journal Neuroscience Section Body Doc Link PMC2568875 Disease Relevance 0.18 Pain Relevance 0.26

We have found that in the absence of MOR activation, the brain specific Galphaz subunit binds to and stabilizes Src in its inactive form.

Positive_regulation (stabilizes) of Src in brain

17) Confidence 0.11 Published 2009 Journal Cell. Signal. Section Abstract Doc Link 19446022 Disease Relevance 0 Pain Relevance 0.35

Internalization and Src activity regulate the time course of ERK activation by delta opioid receptor ligands.

Positive_regulation (activation) of Src associated with opioid receptor

18) Confidence 0.10 Published 2005 Journal J. Biol. Chem. Section Title Doc Link 15632168 Disease Relevance 0 Pain Relevance 0.34

enhances NMDA receptor-mediated Ca2+ responses via activating tyrosine protein kinase Src [94], which is known to enhance NMDA receptor activity in dorsal horn neurons [52, 95].

Positive_regulation (activating) of tyrosine protein kinase Src in dorsal horn associated with nmda receptor and dorsal horn neuron

19) Confidence 0.06 Published 2005 Journal Purinergic Signal Section Body Doc Link PMC2096535 Disease Relevance 0.58 Pain Relevance 0.79

Previously, we showed that selective delta-opioid agonists were able to induce the rapid tyrosine phosphorylation of delta-opioid receptors (delta-ORs) through Src.

Positive_regulation (induce) of Src associated with mu agonist and delta opioid receptors

20) Confidence 0.06 Published 2000 Journal Brain Res. Mol. Brain Res. Section Abstract Doc Link 10925143 Disease Relevance 0 Pain Relevance 0.31

General Comments

This test has worked.