Rho-kinase mediates spinal nitric oxide formation by prostaglandin E2 via EP3 subtype.

Abstract

Prostaglandin E2 (PGE2), the principal pro-inflammatory prostanoid, is known to play versatile roles in pain transmission via four PGE receptor subtypes, EP1-EP4. We recently demonstrated that continuous production of nitric oxide (NO) by neuronal NO synthase (nNOS) following phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS) and NMDA receptor NR2B subunits is essential for neuropathic pain. These phosphorylation and nNOS activity visualized by NADPH-diaphorase histochemistry were blocked by indomethacin, a PG synthesis inhibitor. To clarify the interaction between cyclooxygenase and nNOS pathways in the spinal cord, we examined the effect of EP subtype-selective agonists on NO production. NO formation was stimulated in the spinal superficial layer by EP1, EP3, and EP4 agonists. While the EP1- and the EP4-stimulated NO formation was markedly blocked by MK-801, an NMDA receptor antagonist, the EP3-stimulated one was completely inhibited by H-1152, a Rho-kinase inhibitor. Phosphorylation of MARCKS and NADPH-diaphorase activity stimulated by the EP3 agonist were also blocked by H-1152. These results suggest that PGE2 stimulates NO formation by Rho-kinase via EP3, a mechanism(s) different from EP1 and EP4.

• Authors: Shinji Matsumura, Tetsuya Abe, Tamaki Mabuchi, Tayo Katano, Kunio Takagi, Emiko Okuda-Ashitaka, Shinichi Tatsumi, Yoshihide Nakai, Hiroyoshi Hidaka, Masaaki Suzuki, Yasuharu Sasaki, Toshiaki Minami, Seiji Ito
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 338 Issue 1 Pg. 550-7 (Dec 09 2005) ISSN: 0006-291X [Print] United States
• PMID: 16188227 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Intracellular Signaling Peptides and Proteins
• Marcks protein, mouse
• Membrane Proteins
• Ptger3 protein, mouse
• Receptors, Prostaglandin E
• Receptors, Prostaglandin E, EP3 Subtype
• Myristoylated Alanine-Rich C Kinase Substrate
• Nitric Oxide
• Protein Serine-Threonine Kinases
• rho-Associated Kinases
• Dinoprostone
• Indomethacin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Dinoprostone (physiology)
• Indomethacin (pharmacology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Myristoylated Alanine-Rich C Kinase Substrate
• Nitric Oxide (biosynthesis)
• Phosphorylation
• Protein Serine-Threonine Kinases (chemistry, physiology)
• Receptors, Prostaglandin E (agonists, physiology)
• Receptors, Prostaglandin E, EP3 Subtype
• Spinal Cord (enzymology, metabolism)
• rho-Associated Kinases