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Submitted on February 12, 2004
Accepted on September 27, 2004
-Cells
Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Sciences, Barts and The London, Queen Mary's School of Medicine and Dentistry, University of London, Whitechapel, London, E1 1BB, UK. Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Churchill Hospital, Oxford, OX3 7LJ, UK. Departments of Integrative Biosciences and Ophthalmology, Oregon Health and Science University, Portland, OR 97201, USA
* To whom correspondence should be addressed. E-mail: M.D.Turner{at}qmul.ac.uk.
Calpain-10 (CAPN10) is the first type 2 diabetes susceptibility gene to be identified through a genome scan, with polymorphisms being associated with altered CAPN10 expression. Functional data has been hitherto elusive, but we report here a corresponding increase between CAPN10 expression level and regulated insulin secretion. Pancreatic 
-cell secretory granule exocytosis is mediated by the SNARE protein complex of SNAP-25, syntaxin 1 and VAMP2. We report for the first time direct binding of a calpain-10 isoform with members of this complex. Furthermore SNAP-25 undergoes a Ca2+-dependent partial proteolysis during exocytosis, with calpain protease inhibitor similarly suppressing both insulin secretion and SNAP-25 proteolysis alike. Based upon these findings we postulate that an isoform of calpain-10 is a Ca2+-sensor which functions to trigger exocytosis in pancreatic -cells.
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