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¹ Department of Anatomy and Neurobiology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
² Course of Medical Biosignaling, The Public Relations Committee, Graduate School of Medicine, Faculty of Medicine, Osaka University, 2-2 Yamadaoka Suita, Osaka 565-0871 Japan
³ Molecular Medicine Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan

Phase resetting is one of the essential properties of circadian clocks that is required for the adjustment to a particular environment and the induction of Per1 and Per2 clock genes is believed to be a primary molecular event during this process. Although the intracellular signal transduction pathway underlying Per1 gene activation has been well characterized, the mechanisms that control Per2 up-regulation have not yet been elucidated. In our present study, we demonstrate that Gq/11 coupled receptors mediate serum-induced immediate rat Per2 (rPer2) transactivation in Rat-1 fibroblasts via intracellular Ca²⁺ mobilization. Stimulation of these cells with a high concentration of serum was found to rapidly increase the intracellular Ca²⁺ levels and strongly up-regulated rPer2 gene. rPer2 induction by serum stimulation was abrogated by intracellular Ca²⁺ chelation and depletion of intracellular Ca²⁺ store, which suggests that the calcium mobilization is necessary for the up-regulation of rPer2 gene. In addition, suppression of Gq/11 function was observed to inhibit both Ca²⁺ mobilization and rPer2 induction. Further, we demonstrated that endothelin-induced acute rPer2 transactivation via Gq/11-coupled endothelin receptors is also suppressed by a Gq/11 specific inhibitor. These findings together suggest that serum and endothelin utilize a common Gq/11-PLC mediated pathway for the transactivation of rPer2, which involves the mobilization of calcium from the intracellular calcium store.

^* Correspondence: E-mail: shigey{at}med.kindai.ac.jp