Retinoic acids increase P2X2 receptor expression through the 5'-flanking region of P2rx2 gene in rat phaeochromocytoma PC-12 cells.

The P2X2 receptor is a subtype of ionotropic ATP receptor and plays a significant role in regulating fast synaptic transmission in the nervous system. Because the expression level of the P2X2 receptor is known to determine its channel properties and functional interactions with other neurotransmitter channels, elucidating the mechanisms underlying the regulation of P2X2 receptor expression in neuronal cells is important. Here, we identified three motifs that correspond to the retinoic acid response element in the 5'-flanking region of the rat P2X2 gene. In rat pheochromocytoma PC-12 cells, treatment with 9-cis-retinoic acid as well as all-trans-retinoic acid significantly increased the mRNA and protein level of P2X2 receptor. In addition, in PC-12 cells transiently transfected with a luciferase reporter gene driven by the promoter region of the rat P2X2 gene, both 9-cis-retinoic acid and all-trans-retinoic acid increased the luciferase activity, whereas their effects were diminished by truncation of the retinoic acid response elements in the promoter. Furthermore, 9-cis-retinoic acid enhanced the ATP-evoked whole cell currents and intracellular Ca2+- and ATP-evoked dopamine release, indicating the up-regulation of functional P2X2 receptors on the plasma membrane. These results provide the molecular mechanism underlying the transcriptional regulation of P2X2 receptors and suggest that retinoid is an important factor in regulating P2X2 receptors in the nervous system.