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The Journal of Neuroscience, February 6, 2008, 28(6):1320-1330; doi:10.1523/JNEUROSCI.5037-07.2008

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Behavioral/Systems/Cognitive
Cysteine-Rich Protein 2, a Novel Downstream Effector of cGMP/cGMP-Dependent Protein Kinase I-Mediated Persistent Inflammatory Pain

Achim Schmidtko,¹ Wei Gao,¹ Matthias Sausbier,² Inga Rauhmeier,¹ Ulrike Sausbier,² Ellen Niederberger,¹ Klaus Scholich,¹ Andrea Huber,³ Winfried Neuhuber,⁴ Hans-Dieter Allescher,⁵ Franz Hofmann,³ Irmgard Tegeder,¹ Peter Ruth,² and Gerd Geisslinger¹

¹Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, 60590 Frankfurt am Main, Germany, ²Pharmazeutisches Institut, Pharmakologie und Toxikologie, 72076 Tübingen, Germany, ³Institut für Pharmakologie und Toxikologie, Technische Universität München, 80802 München, Germany, ⁴Institut für Anatomie, Universität Erlangen-Nürnberg, 91054 Erlangen, Germany, and ⁵Zentrum für Innere Medizin, Klinikum Garmisch-Partenkirchen, 82467 Garmisch-Partenkirchen, Germany

Correspondence should be addressed to Dr. Achim Schmidtko, Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Email: Schmidtko{at}em.uni-frankfurt.de

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.

Key words: CRP2; cGKI; spinal cord; DRG; knock-out mice; pain behavior

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Received July 6, 2007; revised Dec. 13, 2007; accepted Dec. 13, 2007.

Correspondence should be addressed to Dr. Achim Schmidtko, Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Email: Schmidtko{at}em.uni-frankfurt.de

This article has been cited by other articles:

				S. Pierre, C. Maeurer, O. Coste, W. Becker, A. Schmidtko, S. Holland, C. Wittpoth, G. Geisslinger, and K. Scholich Toponomics Analysis of Functional Interactions of the Ubiquitin Ligase PAM (Protein Associated with Myc) during Spinal Nociceptive Processing Mol. Cell. Proteomics, December 1, 2008; 7(12): 2475 - 2485. [Abstract] [Full Text] [PDF]

				A. Schmidtko, W. Gao, P. Konig, S. Heine, R. Motterlini, P. Ruth, J. Schlossmann, D. Koesling, E. Niederberger, I. Tegeder, et al. cGMP Produced by NO-Sensitive Guanylyl Cyclase Essentially Contributes to Inflammatory and Neuropathic Pain by Using Targets Different from cGMP-Dependent Protein Kinase I J. Neurosci., August 20, 2008; 28(34): 8568 - 8576. [Abstract] [Full Text] [PDF]

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