title: Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass.
abstract: Understanding the molecular mechanisms that regulate β cell mass and proliferation is important for the treatment of diabetes. Here, we identified domperidone (DPD), a dopamine D2 receptor (DRD2) antagonist that enhances β cell mass. Over time, islet β cell loss occurs in dissociation cultures, and this was inhibited by DPD. DPD increased proliferation and decreased apoptosis of β cells through increasing intracellular cAMP. DPD prevented β cell dedifferentiation, which together highly contributed to the increased β cell mass. DRD2 knockdown phenocopied the effects of domperidone and increased the number of β cells. Drd2 overexpression sensitized the dopamine responsiveness of β cells and increased apoptosis. Further analysis revealed that the adenosine agonist 5'-N-ethylcarboxamidoadenosine, a previously identified promoter of β cell proliferation, acted with DPD to increase the number of β cells. In humans, dopamine also modulates β cell mass through DRD2 and exerts an inhibitory effect on adenosine signaling.
authors.affiliation: Department of Life Science and Technology, School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sakano
authors.affiliation: Division of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
authors.forename: Sungik
authors.initials: S
authors.lastname: Choi
authors.affiliation: Division of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
authors.forename: Masateru
authors.initials: M
authors.lastname: Kataoka
authors.affiliation: Department of Life Science and Technology, School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shiraki
authors.affiliation: Department of Chemical Biology, Institute for Chemical Research, Institute for Integrated Cell-Material Sciences, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Motonari
authors.initials: M
authors.lastname: Uesugi
authors.affiliation: Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe Street, Mizuho, Nagoya 467-8603, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kume
authors.affiliation: Department of Life Science and Technology, School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta, Midori-ku, Yokohama, Kanagawa 226-8501, Japan. Electronic address: skume@bio.titech.ac.jp.
authors.forename: Shoen
authors.initials: S
authors.lastname: Kume
mesh_terms: D000241:Adenosine / Q000819:agonists / Q000378:metabolism; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D004294:Domperidone / Q000008:administration & dosage; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D007328:Insulin; D017448:Receptors, Dopamine D2; D019830:Adenosine-5'-(N-ethylcarboxamide); D004294:Domperidone; D000241:Adenosine; D004298:Dopamine
keywords: apoptosis; dedifferentiation; diabetes; insulin; pancreas; proliferation