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J. Biol. Chem., Vol. 281, Issue 31, 21942-21953, August 4, 2006

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The Neuronal Ca²⁺ Sensor Protein Visinin-like Protein-1 Is Expressed in Pancreatic Islets and Regulates Insulin Secretion^*

Feihan F. Dai¹, Yi Zhang, Youhou Kang, Qinghua Wang, Herbert Y. Gaisano, Karl-Heinz Braunewell, Catherine B. Chan^¶, and Michael B. Wheeler, Recipient of a Canadian Institutes of Health Research investigator award²

From the Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada, the Signal Transduction Research Group, Neuroscience Research Center of the Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany, and the ^¶Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Prince Edward Island C1A 4P3, Canada

Visinin-like protein-1 (VILIP-1) is a member of the neuronal Ca²⁺ sensor protein family that modulates Ca²⁺-dependent cell signaling events. VILIP-1, which is expressed primarily in the brain, increases cAMP formation in neural cells by modulating adenylyl cyclase, but its functional role in other tissues remains largely unknown. In this study, we demonstrate that VILIP-1 is expressed in murine pancreatic islets and -cells. To gain insight into the functions of VILIP-1 in -cells, we used both overexpression and small interfering RNA knockdown strategies. Overexpression of VILIP-1 in the MIN6-cell line or isolated mouse islets had no effect on basal insulin secretion but significantly increased glucose-stimulated insulin secretion. cAMP accumulation was elevated in VILIP-1-overexpressing cells, and the protein kinase A inhibitor H-89 attenuated increased glucose-stimulated insulin secretion. Overexpression of VILIP-1 in isolated mouse -cells increased cAMP content accompanied by increased cAMP-responsive element-binding protein gene expression and enhanced exocytosis as detected by cell capacitance measurements. Conversely, VILIP-1 knockdown by small interfering RNA caused a reduction in cAMP accumulation and produced a dramatic increase in preproinsulin mRNA, basal insulin secretion, and total cellular insulin content. The increase in preproinsulin mRNA in these cells was attributed to enhanced insulin gene transcription. Taken together, we have shown that VILIP-1 is expressed in pancreatic -cells and modulates insulin secretion. Increased VILIP-1 enhanced insulin secretion in a cAMP-associated manner. Down-regulation of VILIP-1 was accompanied by decreased cAMP accumulation but increased insulin gene transcription.

Received for publication, December 2, 2005 , and in revised form, May 9, 2006.

^* This work was supported in part by an operating grant from the Canadian Diabetes Association (to M. B. W.) and Grant MOP-12898 from the Canadian Institutes of Health Research (to M. B. W. and C. B. C.). 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 Figs. 1 and 2.

¹ Supported by New Emerging Teams Grant NET-54012 from the Canadian Institutes of Health Research.

² To whom correspondence should be addressed: Dept. of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-6737; Fax: 416-978-4940; E-mail: michael.wheeler{at}utoronto.ca.

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