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Activity-dependent dephosphorylation of paxillin contributed to nociceptive plasticity in spinal cord dorsal horn

Xin-Tai Wang1, Rui Zheng, Zhan-Wei Suo

  • 1Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, China.

Pain
|February 17, 2016
PubMed

Insights

Paxillin dephosphorylation at Tyr118 regulates pain signaling by controlling C-terminal Src kinase (CSK) localization at synapses. This mechanism impacts Src-dependent nociceptive plasticity and chronic pain development.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pain Research

Background:

  • Protein tyrosine kinase Src activity is regulated by C-terminal Src kinase (CSK) and protein tyrosine phosphatases (PTPs).
  • Aberrant Src activation in the spinal cord dorsal horn contributes to pain sensitization.
  • Paxillin, a cell adhesion molecule, plays a role in cell migration and survival.

Purpose of the Study:

  • To investigate how paxillin integrates CSK and PTP signaling to regulate Src-dependent nociceptive plasticity.
  • To elucidate the role of paxillin phosphorylation at Tyr118 in synaptic localization of CSK.
  • To determine the impact of this pathway on pain signaling and chronic inflammatory pain.

Main Methods:

  • Immunohistochemistry to determine paxillin localization at excitatory synapses.
  • Analysis of paxillin phosphorylation at Tyr118 and its association with CSK.
  • Investigating the effect of paxillin mutations on CSK localization and Src activity in vivo.
  • Assessing synaptic transmission and pain behaviors in mouse models of inflammation.

Main Results:

  • Paxillin localizes at excitatory synapses, and Tyr118 phosphorylation is crucial for targeting CSK to these sites.
  • Peripheral tissue injury leads to N-methyl-D-aspartate (NMDA) receptor activation, PTPs signaling, and Tyr118 dephosphorylation.
  • Reduced Tyr118 phosphorylation causes CSK dispersal, increasing Src activity and potentiating synaptic transmission via GluN2B-containing NMDA receptors.
  • Restoring CSK synaptic localization with a phosphomimicking paxillin mutant reduced Src hyperactivity, blunted NMDA receptor transmission, and alleviated chronic inflammatory pain.

Conclusions:

  • PTPs-mediated dephosphorylation of paxillin at Tyr118 is a key mechanism for modifying nociceptive plasticity.
  • The paxillin-CSK-Src signaling axis at excitatory synapses regulates pain sensitization.
  • Targeting this pathway offers a potential strategy for treating chronic inflammatory pain.

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