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

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 19; no. 1; pp. 213 - 224
• Main Authors: Marshall, Catriona, Hitman, Graham A, Partridge, Christopher J, Clark, Anne, Ma, Hong, Shearer, Thomas R, Turner, Mark D
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-01-2005; Oxford University Press
• Subjects: Antigens, Surface - metabolism; Calcium - pharmacology; Calpain - antagonists & inhibitors; Calpain - metabolism; Cell Line; Cell Membrane - enzymology; Cytosol - enzymology; Exocytosis - drug effects; Gene Expression Regulation - drug effects; Glucose - pharmacology; Humans; Immunohistochemistry; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - enzymology; Islets of Langerhans - metabolism; Membrane Proteins - metabolism; Nerve Tissue Proteins - metabolism; Protein Binding; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Synaptosomal-Associated Protein 25; Syntaxin 1
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2004-0064

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 β-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 β-cells.