title: Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1.
abstract: Contact between β-cells is necessary for their normal function. Identification of the proteins mediating the effects of β-cell-to-β-cell contact is a necessary step toward gaining a full understanding of the determinants of β-cell function and insulin secretion. The secretory machinery of the β-cells is nearly identical to that of central nervous system (CNS) synapses, and we hypothesize that the transcellular protein interactions that drive maturation of the two secretory machineries upon contact of one cell (or neural process) with another are also highly similar. Two such transcellular interactions, important for both synaptic and β-cell function, have been identified: EphA/ephrin-A and neuroligin/neurexin. Here, we tested the role of another synaptic cleft protein, CADM1, in insulinoma cells and in rat and human islet β-cells. We found that CADM1 is a predominant CADM isoform in β-cells. In INS-1 cells and primary β-cells, CADM1 constrains insulin secretion, and its expression decreases after prolonged glucose stimulation. Using a coculture model, we found that CADM1 also influences insulin secretion in a transcellular manner. We asked whether extracellular CADM1 interactions exert their influence via the same mechanisms by which they influence neurotransmitter exocytosis. Our results suggest that, as in the CNS, CADM1 interactions drive exocytic site assembly and promote actin network formation. These results support the broader hypothesis that the effects of cell-cell contact on β-cell maturation and function are mediated by the same extracellular protein interactions that drive the formation of the presynaptic exocytic machinery. These interactions may be therapeutic targets for reversing β-cell dysfunction in diabetes.
authors.affiliation: Department of Medicine, University of California, Irvine, School of Medicine, Irvine, California;
authors.forename: Charles
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of California, Irvine, School of Medicine, Irvine, California;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Caldwell
authors.affiliation: Department of Medicine, University of California, Irvine, School of Medicine, Irvine, California;
authors.forename: M Reza
authors.initials: MR
authors.lastname: Mirbolooki
authors.affiliation: Pediatric Diabetes Research Center, University of California San Diego, La Jolla, California; and.
authors.forename: Diana
authors.initials: D
authors.lastname: Duong
authors.affiliation: Department of Medicine, University of California, Irvine, School of Medicine, Irvine, California;
authors.forename: Eun Jee
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Research Service, Veterans Affairs San Diego Healthcare System, San Diego, California.
authors.forename: Nai-Wen
authors.initials: NW
authors.lastname: Chi
authors.affiliation: Department of Medicine, University of California, Irvine, School of Medicine, Irvine, California; s.chessler@uci.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Chessler
mesh_terms: D000818:Animals; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D002460:Cell Line; D005089:Exocytosis / Q000502:physiology*; D045604:Extracellular Fluid / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity; D050827:Syntaxin 1 / Q000378:metabolism*
chemical_list: C403514:CADM1 protein, human; C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D007328:Insulin; D050827:Syntaxin 1
keywords: SynCam; cell adhesion molecule 1; insulin secretion; pancreatic islet