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Retinoic Acids Increase P2X₂ Receptor Expression through the 5'-Flanking Region of P2rx2 Gene in Rat Phaeochromocytoma PC-12 Cells

Divisions of Pharmacology (H.T.-S., S.K.) and Cellular and Gene Therapy Products (Y.S.), National Institute of Health Sciences, Tokyo, Japan; National Institute of Health Sciences, Tokyo, Japan (T.N.); and Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (H.T.-S., M.T., K.I.)

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.

Address correspondence to: Dr. Kazuhide Inoue, Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan. E-mail: inoue{at}phar.kyushu-u.ac.jp