Persistent inflammation-induced upregulation of BDNF promotes synaptic delivery of {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor GluA1 subunits in descending pain modulatory circuits [Molecular Bases of Disease]

June 25th, 2014 by Tao, W., Chen, Q., Zhou, W., Wang, Y., Wang, L., Zhang, Z.

The enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation at GluA1 serine 831 sites in the central pain-modulating system plays a pivotal role in descending pain facilitation after inflammation, but the underlying mechanisms remain unclear. It is here shown that, in the rat brainstem nucleus raphe magnus (NRM), which is a critical relay in the brain descending pain-modulating system, persistent inflammatory pain induced by complete Freund adjuvant (CFA) can enhance AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) and GluA2-lacking AMPA receptor-mediated rectification index. Western blot analysis showed an increase in GluA1 phosphorylation at Ser-831 but not on Ser-845. This was accompanied by an increase in distribution of the synaptic GluA1 subunit. In parallel, the level of histone H3 acetylation at brain-derived neurotrophic factor (Bdnf) gene promoter regions was significantly reduced 3 days after CFA injection, as indicated by chromatin immunoprecipitation (CHIP) assays. This was correlated with an increase in BDNF mRNA levels and BDNF protein levels. Sequestering endogenous extracellular BDNF with TrkB-IgG in the NRM decreased AMPA receptor-mediated synaptic transmission and GluA1 phosphorylation at Ser-831 3 days after CFA injection. Under the same conditions, blockade of TrkB receptor functions, phospholipase C (PLC) or protein kinase C (PKC) impaired GluA1 phosphorylation at Ser-831 and decreased EPSCs mediated by GluA2-lacking AMPA receptors. Taken together, these results suggest that epigenetic upregulation of BDNF by peripheral inflammation induces GluR1 phosphorylation at Ser-831 sites through activation of the PLC-PKC signaling cascade, leading to the trafficking of GluA1 to pain-modulating neuronal synapses.
  • Posted in Journal of Biological Chemistry, Publications
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