Cysteine-rich protein 2, a novel downstream effector of cGMP/cGMP-dependent protein kinase I-mediated persistent inflammatory pain.
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.
Schmidtko
Achim
A
Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, 60590 Frankfurt am Main, Germany. Schmidtko@em.uni-frankfurt.de
Gao
Wei
W
Sausbier
Matthias
M
Rauhmeier
Inga
I
Sausbier
Ulrike
U
Niederberger
Ellen
E
Scholich
Klaus
K
Huber
Andrea
A
Neuhuber
Winfried
W
Allescher
Hans-Dieter
HD
Hofmann
Franz
F
Tegeder
Irmgard
I
Ruth
Peter
P
Geisslinger
Gerd
G
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
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