RT Journal Article
SR Electronic
T1 p38β MAPK signaling mediates exenatide-stimulated microglial β-endorphin expression
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.116.107102
DO 10.1124/mol.116.107102
A1 Hai-Yun Wu
A1 Xiao-Fang Mao
A1 Hui Fan
A1 Yong-Xiang Wang
YR 2017
UL http://molpharm.aspetjournals.org/content/early/2017/02/15/mol.116.107102.abstract
AB Upon recent discovery, it has been established that activation of glucagon-like peptide-1 receptors (GLP-1Rs) exhibits neuroprotection and antinociception through microglial β-endorphin expression. This study aims to explore its underlying signaling mechanisms. GLP-1Rs and β-endorphin were co-expressed in primary cultures of microglia. Treatment with the GLP-1R agonist exenatide concentration-dependently stimulated microglial expression of the β-endorphin precursor gene POMC and peptide, with EC50 values of 4.1 and 7.5 nM, respectively. Exenatide also significantly increased intracellular cAMP levels and expression of p-PKA, p-p38 and p-CREB in cultured primary microglia. Furthermore, exenatide-induced microglial expression of POMC was completely blocked by reagents that specifically inhibit adenylyl cyclase and activation of PKA, p38 and CREB. In addition, exenatide-induced microglial p38 phosphorylation and POMC expression were eliminated by knockdown of p38α (but not p38α) using siRNA. In contrast, LPS-increased microglial activation of p38 and expression of proinflammatory factors (including TNF-α, IL-1β and IL-6) were partially suppressed by knockdown of p38α (but not p38β). Exenatide-induced phosphorylation of p38 and CREB was also totally blocked by the PKA inhibitor and siRNA/p38β, but not by siRNA/p38α. The 7-day intrathecal injections of siRNA/p38β (but not siRNA/p38α) completely blocked exenatide-induced spinal p38 activation, β-endorphin expression and mechanical antiallodynia in rats of established neuropathy, although siRNA/p38β and siRNA/p38α were not antiallodynia. Our results, for the first time, have drawn a causal relationship between the PKA-dependent p38β MAPK/CREB signal cascade and GLP-1R agonism-mediated microglial β-endorphin expression. Differential role of p38α and p38β activation in inflammation and nociception was also highlighted.