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

Abstract

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.

• Authors: Achim Schmidtko, Wei Gao, Matthias Sausbier, Inga Rauhmeier, Ulrike Sausbier, Ellen Niederberger, Klaus Scholich, Andrea Huber, Winfried Neuhuber, Hans-Dieter Allescher, Franz Hofmann, Irmgard Tegeder, Peter Ruth, Gerd Geisslinger
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 28 Issue 6 Pg. 1320-30 (Feb 06 2008) ISSN: 1529-2401 [Electronic] United States
• PMID: 18256252 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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