title: Opposing roles for SNAP23 in secretion in exocrine and endocrine pancreatic cells.
abstract: The membrane fusion of secretory granules with plasma membranes is crucial for the exocytosis of hormones and enzymes. Secretion disorders can cause various diseases such as diabetes or pancreatitis. Synaptosomal-associated protein 23 (SNAP23), a soluble N-ethyl-maleimide sensitive fusion protein attachment protein receptor (SNARE) molecule, is essential for secretory granule fusion in several cell lines. However, the in vivo functions of SNAP23 in endocrine and exocrine tissues remain unclear. In this study, we show opposing roles for SNAP23 in secretion in pancreatic exocrine and endocrine cells. The loss of SNAP23 in the exocrine and endocrine pancreas resulted in decreased and increased fusion of granules to the plasma membrane after stimulation, respectively. Furthermore, we identified a low molecular weight compound, MF286, that binds specifically to SNAP23 and promotes insulin secretion in mice. Our results demonstrate opposing roles for SNAP23 in the secretion mechanisms of the endocrine and exocrine pancreas and reveal that the SNAP23-binding compound MF286 may be a promising drug for diabetes treatment.
authors.affiliation: Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masataka
authors.identifier: http://orcid.org/0000-0001-7222-7456
authors.initials: M
authors.lastname: Kunii
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
authors.forename: Mica
authors.initials: M
authors.lastname: Ohara-Imaizumi
authors.affiliation: Laboratory of Structural Physiology, Graduate School of Medicine, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Molecular and Cellular Biophysics, Research Institute for Electronic Science, Hokkaido University, Hokkaido 001-0020, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kawakami
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Kanagawa 223-8522, Japan.
authors.forename: Siro
authors.initials: S
authors.lastname: Simizu
authors.affiliation: Drug Discovery Team, Office for University-Industry Collaboration Planning and Promotion, Osaka University, Osaka 565-0871, Japan.
authors.forename: Bangzhong
authors.initials: B
authors.lastname: Lin
authors.affiliation: Drug Discovery Team, Office for University-Industry Collaboration Planning and Promotion, Osaka University, Osaka 565-0871, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nunomura
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
authors.forename: Kyota
authors.initials: K
authors.lastname: Aoyagi
authors.affiliation: Laboratory of Structural Physiology, Graduate School of Medicine, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohmuraya
authors.affiliation: Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Shin-Ichiro
authors.identifier: http://orcid.org/0000-0003-3632-0674
authors.initials: SI
authors.lastname: Yoshimura
authors.affiliation: Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan Department of Judo Therapy, Takarazuka University of Medical and Health Care, Hyogo 666-0152, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Harada
authors.affiliation: Drug Discovery Team, Office for University-Industry Collaboration Planning and Promotion, Osaka University, Osaka 565-0871, Japan.
authors.forename: Yoon-Jeong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.affiliation: Laboratory of Molecular and Cellular Biophysics, Research Institute for Electronic Science, Hokkaido University, Hokkaido 001-0020, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Nemoto
authors.affiliation: Laboratory of Structural Physiology, Graduate School of Medicine, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Haruo
authors.identifier: http://orcid.org/0000-0003-2327-9027
authors.initials: H
authors.lastname: Kasai
authors.affiliation: Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagamatsu
authors.affiliation: Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan aharada@acb.med.osaka-u.ac.jp.
authors.forename: Akihiro
authors.identifier: http://orcid.org/0000-0002-2484-9784
authors.initials: A
authors.lastname: Harada
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000648:ultrastructure; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002459:Cell Fusion; D005089:Exocytosis; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology*; D018345:Mice, Knockout; D036641:Microscopy, Fluorescence, Multiphoton; D008954:Models, Biological; D046790:Pancreas, Exocrine / Q000166:cytology*; D010306:Parotid Gland / Q000166:cytology; D021381:Protein Transport; D050766:Qb-SNARE Proteins / Q000172:deficiency / Q000378:metabolism*; D050767:Qc-SNARE Proteins / Q000172:deficiency / Q000378:metabolism*; D050600:SNARE Proteins / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; D050600:SNARE Proteins; C495693:Slc2a4 protein, mouse; C107017:Snap23 protein, mouse; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D000681:Amylases