cAMP-dependent protein kinase activated Fyn in spinal dorsal horn to regulate NMDA receptor function during inflammatory pain.
Selective inhibition of GluN2B-containing NMDA receptor (GluN2BR) in spinal dorsal horn effectively alleviates inflammatory pain, suggesting the up-regulation of GluN2BR function involved in central sensitization. Previous studies have demonstrated that the increase in GluN2BR synaptic expression serves as a key step to enhance GluN2BR function after intradermal injection of Complete Freund's Adjuvant (CFA). Here, we showed that cAMP-dependent protein kinase (PKA) played an important role in redistributing GluN2BR at synapses, because inhibition of PKA activity impaired GluN2BR accumulation at post-synaptic density (PSD)-enriched fraction in CFA-injected mice, and direct stimulation of PKA in naïve mice mimicked the effect of CFA by recruiting GluN2BR at PSD fraction to evoke pain sensitization. Analysis of PKA-initiated signalings unraveled that PKA was able to activate Src-family protein tyrosine kinases member Fyn, possibly by disrupting Fyn association with its inhibitory partner striatal-enriched protein tyrosine phosphatase 61. The active Fyn then promoted GluN2B phosphorylation at Tyr1472, a molecular event known to prevent GluN2BR endocytosis. As a result, pharmacological or genetic manipulation of Fyn activity greatly depressed GluN2BR accumulation at PSD-enriched fraction and ameliorated mechanical allodynia induced by PKA. Our data thus elucidated a critical role of PKA/Fyn/GluN2B signaling in triggering GluN2BR hyperfunction and pain hypersensitivity.
Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China.
Hong-Bin
HB
Yang
Xian
X
Yang
Jing
J
Cao
Shuai
S
Li
Yan-Ni
YN
Liu
Zhan-Wei
ZW
Suo
Hong-Bin
HB
Cui
Zhong
Z
Guo
Xiao-Dong
XD
Hu
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000201:enzymology / Q000378:metabolism*; D020671:Posterior Horn Cells / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism
D016194:Receptors, N-Methyl-D-Aspartate; D051076:Proto-Oncogene Proteins c-fyn; D017868:Cyclic AMP-Dependent Protein Kinases