Dopamine D1 receptors regulate type 1 inositol 1,4,5‐trisphosphate receptor expression via both AP‐1‐ and NFATc4‐mediated transcriptional processes

Abstract

Although our recent report demonstrates the essential involvement of up-regulation of a regulator of intracellular Ca(2+) concentration, type 1 inositol 1,4,5-trisphosphate receptors (IP(3) Rs-1), mediated via dopamine D1-like receptor (D1DR) stimulation in the cocaine-induced psychological dependence, the exact mechanisms of regulation of IP(3) R-1 expression by D1DRs have not yet been clarified. This study attempted to clarify these mechanisms using mouse cerebral cortical neurons. An agonist for phosphatidylinositide-linked D1DRs, SKF83959, induced dose- and time-dependently IP(3) R-1 protein up-regulation following its mRNA increase without cAMP production. U73122 (a phospholipase C inhibitor), BAPTA-AM (an intracellular calcium chelating reagent), W7 (a calmodulin inhibitor), KN-93 (a calmodulin-dependent protein kinases inhibitor), and FK506 (a calcineurin inhibitor), significantly inhibited the SKF83959-induced IP(3) R-1 up-regulation. Furthermore, immunohistochemical examinations showed that SKF83959 increased expression of both cFos and cJun in nucleus as well as enhanced translocation of both calcineurin and NFATc4 complex to nucleus from cytoplasm. In addition, SKF83959 directly recruited binding of both AP-1 and NFATc4 to IP(3) R-1 promoter region. These results indicate that D1DR activation induces IP(3) R-1 up-regulation via increased translocation of AP-1 as well as NFATc4 in Gαq protein-coupled calcium signaling transduction pathway.