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Cofilin phosphorylation is involved in nitric oxide/cGMP-mediated nociception

Lars Zulauf1, Ovidiu Coste, Claudiu Marian

  • 1Pharmazentrum frankfurt/ZAFES, Klinikum der Goethe-Universität, Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany. l.zulauf@hotmail.de

Biochemical and Biophysical Research Communications
|November 10, 2009
PubMed

Insights

Nitric oxide (NO) activates protein kinase I (PKG-I), influencing cofilin phosphorylation and neurite outgrowth. This pathway, involving cofilin, plays a role in inflammatory pain and nociception.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Nitric oxide (NO), cGMP, and cGMP-dependent protein kinase I (PKG-I) are implicated in hyperalgesia.
  • Downstream targets of the NO/cGMP/PKG pathway in nociception remain largely unidentified.
  • Neurite outgrowth, regulated by the NO/cGMP/PKG cascade, is linked to nociception mechanisms.

Purpose of the Study:

  • To investigate the impact of PKG-I activation on the actin cytoskeleton, specifically cofilin.
  • To explore the role of cofilin in inflammatory hyperalgesia.
  • To elucidate the NO-dependent effects on cofilin in vitro and in vivo.

Main Methods:

  • Investigated cofilin phosphorylation and neurite outgrowth in primary rat neurons treated with 8-Br-cGMP (PKG-I activator).
  • Analyzed signal transduction pathways involving Rho-GTPases (RhoA, Rac1, Cdc42) and their targets (ROCK, PAK).
  • Assessed cofilin phosphorylation in rat spinal cords and antinociceptive effects in a zymosan-induced paw inflammation model using l-NAME and Y-27632.

Main Results:

  • PKG-I activation by 8-Br-cGMP increased cofilin phosphorylation and neurite outgrowth in primary neurons.
  • Signal transduction involved RhoA, Rac1, Cdc42, ROCK, and PAK activation.
  • In vivo, l-NAME and Y-27632 reduced spinal cord cofilin phosphorylation and produced antinociceptive effects.

Conclusions:

  • Cofilin is a downstream target of the NO/cGMP/PKG signaling pathway in neurons.
  • Cofilin is involved in NO-mediated nociception and inflammatory hyperalgesia.
  • Targeting the cofilin pathway may offer therapeutic strategies for pain management.

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