Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.

Stimulation of retinoic acid receptors (RARs) protects midbrain dopaminergic neurons, presumably via up-regulation of brain-derived neurotrophic factor (BDNF) expression. The present study was focused on unexplored signaling mechanisms linking RAR stimulation to BDNF expression. Rat midbrain slice cultures treated with an RAR agonist Am80 showed increased tissue levels of BDNF mRNA and protein as compared to cultures without treatment. Am80-induced increase in BDNF expression was observed in dopaminergic neurons, which was blocked by inhibition of extracellular signal-regulated kinase (ERK) activation. We also found that Am80 increased neuronal nitric oxide synthase expression in dopaminergic neurons even during ERK inhibition, and this increase was accompanied by 8-nitro-cyclic GMP formation. Notably, the effect of Am80 on BDNF expression was attenuated by inhibitors of nitric oxide synthase, soluble guanylyl cyclase and cyclic GMP-dependent protein kinase (PKG). Am80-induced ERK phosphorylation in dopaminergic neurons was also attenuated by inhibition of soluble guanylyl cyclase and PKG. Moreover, 8-Br-cyclic GMP induced ERK phosphorylation and BDNF expression in dopaminergic neurons. These results suggest that, by recruiting cyclic GMP and PKG, neuronal nitric oxide synthase-derived nitric oxide plays a novel and essential role in RAR signaling leading to ERK-dependent BDNF up-regulation in midbrain dopaminergic neurons.