title: 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.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, 60590 Frankfurt am Main, Germany. Schmidtko@em.uni-frankfurt.de
authors.forename: Achim
authors.initials: A
authors.lastname: Schmidtko
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Matthias
authors.initials: M
authors.lastname: Sausbier
authors.forename: Inga
authors.initials: I
authors.lastname: Rauhmeier
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sausbier
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.forename: Andrea
authors.initials: A
authors.lastname: Huber
authors.forename: Winfried
authors.initials: W
authors.lastname: Neuhuber
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Allescher
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000818:Animals; D002908:Chronic Disease; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D005727:Ganglia, Spinal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology*; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010146:Pain / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D010523:Peripheral Nervous System Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
chemical_list: C484375:Csrp2 protein, rat; D018836:Inflammation Mediators; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D006152:Cyclic GMP