Molecular mechanism of insulin secretion by a novel target of HNF1 colectrin

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Mutations in the HNF-1a gene cause a monogenic form of type 2 diabetes, maturity-onset diabetes of the young (MODY),characterized by impaired insulin secretion. The molecular mechanism of MODY3 is not fully understood. To identify novel molecular mechanisms of insulin secretion by HNF-1,we screened the downstream target genes of HNF-1a transcription factor by PCR-based suppression subtraction hybridization technique.We found that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1a in pancreatic b-cells. Expression of collectrin was decreased in the islets of HNF-1a KO mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in INS-1 b-cells or in the b-cells of transgenic mice enhanced glucose-stimulated insulin edxocytosis, without affecting Ca2+ influx. Coversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.