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J. Biol. Chem., Vol. 282, Issue 17, 12717-12724, April 27, 2007

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Inhibition of Insulin Secretion by Betagranin, an N-terminal Chromogranin A Fragment^*

Gerhard M. Schmid, Paolo Meda¹, Dorothée Caille, Ed Wargent^¶, Jacqueline O'Dowd^¶, Denis F. Hochstrasser, Michael A. Cawthorne^¶2, and Jean-Charles Sanchez, Supported by grants from Proteome Sciences plc (Cobham, Surrey, UK) and the Swiss National Science Foundation (3100A0-104214)³

From the Biomedical Proteomics Research Group (BPRG), Department of Structural Biology and Bioinformatics, Geneva University Medical Center, CH-1211 Geneva 4, Switzerland, the Department of Cell Physiology and Metabolism, Geneva University Medical Center, CH-1211 Geneva 4, Switzerland, and the ^¶Clore Laboratory, School of Science, Buckingham University, Buckingham MK18 IEG, United Kingdom

Betagranin, an N-terminal fragment of chromogranin A, results from a proteolytic processing, and is co-secreted with insulin. While other chromogranin A-derived peptides negatively modulate hormone secretion, the role of betagranin in pancreatic -cells is so far unknown. We have recently shown that pancreatic islet betagranin levels are down-regulated in obese, leptin-deficient mice. In the present study, we have investigated the distribution of betagranin in primary mouse islets and cells of the MIN6 line and have evaluated its effects on insulin secretion. We showed that betagranin co-localizes with insulin within secretory granules and strongly inhibited insulin secretion in response to both glucose and potassium, by blocking the influx of calcium. The data demonstrated a hitherto unknown inhibitory effect of betagranin on insulin secretion.

Received for publication, January 26, 2007

^* 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.

¹ Supported by grants from the Swiss National Science Foundation (31-0000-109402), the Juvenile Diabetes Research Foundation (1-2005-46 and 1-2007-158), Novo Nordisk, and the Geneva Program for Metabolic Disorders (GeMet).

² Supported by a grant from Proteome Sciences plc (Cobham, Surrey, UK).

³ To whom correspondence should be addressed: Biomedical Proteomic Research Group (BPRG), Dept. of Structural Biology and Bioinformatics, Geneva University Medical Center, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. Tel.: 41-22-379-54-86; Fax: 41-22-379-59-84; E-mail: Jean-Charles.Sanchez{at}medecine.unige.ch.

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