Cysteine-rich protein 2, a novel downstream effector of cGMP/cGMP-dependent protein kinase I-mediated persistent inflammatory pain

J Neurosci. 2008 Feb 6;28(6):1320-30. doi: 10.1523/JNEUROSCI.5037-07.2008.


The cGMP/cGMP-dependent protein kinase I (cGKI) signaling pathway plays an important role in spinal nociceptive processing. However, downstream targets of cGKI in this context have not been identified to date. Using a yeast two-hybrid screen, we isolated cysteine-rich protein 2 (CRP2) as a novel cGKI interactor in the spinal cord. CRP2 is expressed in laminas I and II of the mouse spinal cord and is colocalized with cGKI, calcitonin gene-related peptide, and isolectin B4. Moreover, the majority of CRP2 mRNA-positive dorsal root ganglion (DRG) neurons express cGKI and peripherin. CRP2 is phosphorylated in a cGMP-dependent manner, and its expression increases in the spinal cord and in DRGs after noxious stimulation of a hindpaw. To elucidate the functional role of CRP2 in nociception, we analyzed mice with a targeted deletion of CRP2. CRP2-deficient (CRP2-/-) mice demonstrate normal behavioral responses to acute nociception and after axonal injury of the sciatic nerve, but increased nociceptive behavior in models of inflammatory hyperalgesia compared with wild-type mice. Intrathecal administration of cGMP analogs increases the nociceptive behavior in wild-type but not in CRP2-/- mice, indicating that the presence of CRP2 is important for cGMP-mediated nociception. These data suggest that CRP2 is a new downstream effector of cGKI-mediated spinal nociceptive processing and point to an inhibitory role of CRP2 in the generation of inflammatory pain.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Cyclic GMP / antagonists & inhibitors
  • Cyclic GMP / physiology*
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases / genetics
  • Cyclic GMP-Dependent Protein Kinases / physiology*
  • Ganglia, Spinal / enzymology
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Inflammation Mediators / physiology*
  • LIM Domain Proteins
  • Mice
  • Mice, Knockout
  • Muscle Proteins / genetics
  • Muscle Proteins / physiology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Pain / enzymology*
  • Pain / pathology
  • Pain / prevention & control*
  • Peripheral Nervous System Diseases / enzymology
  • Peripheral Nervous System Diseases / pathology
  • Peripheral Nervous System Diseases / prevention & control
  • Rats
  • Signal Transduction / physiology*
  • Spinal Cord / enzymology
  • Spinal Cord / metabolism
  • Spinal Cord / pathology


  • Csrp2 protein, rat
  • Inflammation Mediators
  • LIM Domain Proteins
  • Muscle Proteins
  • Nuclear Proteins
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases
  • Prkg1 protein, mouse
  • Cyclic GMP