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Evidence that an Isoform of Calpain-10 Is a Regulator of Exocytosis in Pancreatic ß-Cells

Centre for Diabetes and Metabolic Medicine (C.M., G.A.H., M.D.T.), Institute of Cell and Molecular Science, Barts and The London, Queen Mary’s School of Medicine and Dentistry, University of London, Whitechapel, London E1 1BB, United Kingdom; Diabetes Research Laboratories (C.J.P., A.C.), Oxford Centre for Diabetes, Endocrinology and Churchill Hospital, Oxford OX3 7LJ, United Kingdom; and Departments of Integrative Biosciences and Ophthalmology (H.M., T.R.S.), Oregon Health and Science University, Portland, Oregon 97201

Address all correspondence and requests for reprints to: Dr. Mark D. Turner, Centre for Diabetes and Metabolic Medicine, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom. 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 have been hitherto elusive, but we report here a corresponding increase between CAPN10 expression level and regulated insulin secretion. Pancreatic ß-cell secretory granule exocytosis is mediated by the soluble N-ethylmaleimide-sensitive fusion protein attachment receptor protein complex of synaptosomal-associated protein of 25 kDa (SNAP-25), syntaxin 1, and vesicle-associated membrane protein 2. 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. Based upon these findings, we postulate that an isoform of calpain-10 is a Ca²⁺-sensor that functions to trigger exocytosis in pancreatic ß-cells.

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