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J. Biol. Chem., Vol. 279, Issue 44, 46271-46279, October 29, 2004

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Regulation of Type VI Adenylyl Cyclase by Snapin, a SNAP25-binding Protein^*

Jui-ling Chou¶, Chuen-Lin Huang, Hsing-Lin Lai, Amos C. Hung, Chen-Li Chien, Yu-Ya Kao, and Yijuang Chern||

From the Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, the Institute of Neuroscience, National Yang-Ming University, Taipei 112, Taiwan, and the ^¶Department of Medical Technology, Yuanpei University of Science and Technology, Hsinchu 300, Taiwan

In the present study, we used the N terminus (amino acids 1160) of type VI adenylyl cyclase (ACVI) as bait to screen a mouse brain cDNA library and identified Snapin as a novel ACVI-interacting molecule. Snapin is a binding protein of SNAP25, a component of the SNARE complex. Co-immunoprecipitation analyses confirmed the interaction between Snapin and full-length ACVI. Mutational analysis revealed that the interaction domains of ACVI and Snapin were located within amino acids 186 of ACVI and 33–51 of Snapin, respectively. Co-localization of ACVI and Snapin was observed in primary hippocampal neurons. Moreover, expression of Snapin specifically eliminated protein kinase C (PKC)-mediated suppression of ACVI, but not that of cAMP-dependent protein kinase (PKA) or calcium. Mutation of the potential PKC and PKA phosphorylation sites of Snapin did not affect the ability of Snapin to reverse the PKC inhibitory effect on ACVI. Phosphorylation of Snapin by PKC or PKA therefore might not be crucial for Snapin action on ACVI. In contrast, Snapin_33–51, which harbors an internal deletion of amino acids 33–51 did not affect PKC-mediated inhibition of ACVI, supporting that amino acids 33–51 of Snapin comprises the ACVI-interacting region. Consistently, Snapin exerted no effect on PKC-mediated inhibition of an ACVI mutant (ACVI-A87), which lacked the Snapin-interacting region (amino acids 1–86). Snapin thus reverses its action via direct interaction with the N terminus of ACVI. Collectively, we demonstrate herein that in addition to its association with the SNARE complex, Snapin also functions as a regulator of an important cAMP synthesis enzyme in the brain.

Received for publication, June 28, 2004

^* This work was supported by Grants NSC89-2320-B001-011 and NSC90–2320-B001-009 from the National Science Council and Grants NHRI-EX92-9203NI and NHRI-EX93-9203NI from the National Health Research Institutes and Academia Sinica, Taipei, Taiwan. 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Materials.

^|| To whom correspondence should be addressed. Tel.: 886-2-26523913; Fax: 886-2-27829143; E-mail: bmychern{at}ibms.sinica.edu.tw.

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