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J. Biol. Chem., Vol. 279, Issue 46, 47856-47865, November 12, 2004

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Activity-dependent Transcriptional Activation and mRNA Stabilization for Cumulative Expression of Pituitary Adenylate Cyclase-activating Polypeptide mRNA Controlled by Calcium and cAMP Signals in Neurons^*

Mamoru Fukuchi, Akiko Tabuchi, and Masaaki Tsuda¶

From the Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 931-0194 and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corp., Shibuya 3-13-11, Tokyo 150-0002, Japan

Although it has been established that an activity-dependent gene transcription is induced by the calcium (Ca²⁺) signals in neurons, it is unclear how the specific mRNA moieties are transiently accumulated in response to synaptic transmission which evokes multiple intracellular signals including Ca²⁺ and cAMP ones. The expression of pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide, is controlled by Ca²⁺ signals evoked via membrane depolarization in neurons, and, in cultured rat cortical neuronal cells, we found that the Ca²⁺ signal-mediated activation of the PACAP gene promoter was critically controlled by a single cAMP-response element (CRE) located at around –200, to which the CRE-binding protein predominantly bound. The Ca²⁺ signal-induced expression of PACAP mRNA was enhanced by forskolin, which evokes cAMP signals. In support, the PACAP gene promoter was synergistically enhanced by Ca²⁺ and cAMP signals through the CRE, accompanying a prolonged activation of extracellular signal-related protein kinase 1/2 and CRE-binding protein. On the other hand, sole administration of forskolin markedly reduced the cellular content of PACAP mRNA, which was restored by the addition of Ca²⁺ signals. We found that the stability of PACAP mRNA was increased in response to Ca²⁺ signals but not that of activity-regulated cytoskeleton-associated protein (Arc) mRNA, indicating an activity-dependent stabilization of specific mRNA species in neurons, which can antagonize the regulation mediated by cAMP signals. Thus, the transcriptional activation and mRNA stabilization are coordinately regulated by Ca²⁺ and cAMP signals for the cumulative expression of PACAP mRNA in neurons.

Received for publication, August 9, 2004

^* This study was supported by a grant-in-aid for Core Research for Evolutional Science and Technology (CREST) from the Science and Technology Corporation of Japan, Japan and a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 81-76-434-7535; Fax: 81-76-434-5048; E-mail: tsuda{at}ms.toyama-mpu.ac.jp.

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