title: Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet α-cells and prevents their excessive secretion of glucagon.
abstract: Cell adhesion molecule-1 (CADM1) is a recently identified adhesion molecule of pancreatic islet α-cells that mediates nerve-α-cell interactions via trans-homophilic binding and serves anatomical units for the autonomic control of glucagon secretion. CADM1 also mediates attachment between adjacent α-cells. Since gap junctional intercellular communication (GJIC) among islet cells is essential for islet hormone secretion, we examined whether CADM1 promotes GJIC among α-cells and subsequently participates in glucagon secretion regulation. Dye transfer assays using αTC6 mouse α-cells, which endogenously express CADM1, supported this possibility; efficient cell-to-cell spread of gap junction-permeable dye was detected in clusters of αTC6 cells transfected with nonspecific, but not with CADM1-targeting, siRNA. Immunocytochemical analysis of connexin 36, a major component of the gap junction among αTC6 cells, revealed that it was localized exclusively to the cell membrane in CADM1-non-targeted αTC6 cells, but diffusely to the cytoplasm in CADM1-targeted cells. Next, we incubated CADM1-targeted and non-targeted αTC6 cells in a medium containing 1 mM glucose and 200 mM arginine for 30 min to induce glucagon secretion, and found that the targeted cells secreted three times more glucagon than did the non-targeted. We conducted similar experiments using pancreatic islets that were freshly isolated from wild-type and CADM1-knockout mice, and expressed glucagon secretion as ratios relative to baseline values. The increase in ratio was larger in CADM1-knockout islets than in wild-type islets. These results suggest that CADM1 may serve as a volume limiter of glucagon secretion by sustaining α-cell attachment necessary for efficient GJIC.
authors.affiliation: Division of Molecular Pathology; Institute of Medical Science; University of Tokyo; Tokyo, Japan; Department of Pathology; Faculty of Medicine; Kinki University; Osaka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.affiliation: Division of Molecular Pathology; Institute of Medical Science; University of Tokyo; Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ichiyanagi
authors.affiliation: Division of Molecular Pathology; Institute of Medical Science; University of Tokyo; Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Division of Molecular Pathology; Institute of Medical Science; University of Tokyo; Tokyo, Japan; Department of Pathology; Faculty of Medicine; Kinki University; Osaka, Japan.
authors.forename: Man
authors.initials: M
authors.lastname: Hagiyama
authors.affiliation: Department of Pathology; Faculty of Medicine; Kinki University; Osaka, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Division of Molecular Pathology; Institute of Medical Science; University of Tokyo; Tokyo, Japan.
authors.forename: Keiko B
authors.initials: KB
authors.lastname: Kimura
authors.affiliation: Department of Pathology; Faculty of Medicine; Kinki University; Osaka, Japan; Department of Molecular Genetics; Research Institute for Microbial Diseases; Osaka University; Osaka, Japan.
authors.forename: Minami A
authors.initials: MA
authors.lastname: Sakurai
authors.affiliation: Department of Community Health and Gerontological Nursing; Faculty of Medicine; Oita University; Oita, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hamaguchi
authors.affiliation: Division of Molecular Pathology; Institute of Medical Science; University of Tokyo; Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D017630:Connexins / Q000032:analysis; D003593:Cytoplasm / Q000737:chemistry; D017629:Gap Junctions / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000737:chemistry / Q000378:metabolism*; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering; D000097004:Gap Junction delta-2 Protein
chemical_list: D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D017630:Connexins; D005934:Glucagon; D007136:Immunoglobulins; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D000097004:Gap Junction delta-2 Protein; C498598:Cadm1 protein, mouse