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Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass
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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944721/ https://www.ncbi.nlm.nih.gov/pubmed/27373926 http://dx.doi.org/10.1016/j.stemcr.2016.05.015 |
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author | Sakano, Daisuke Choi, Sungik Kataoka, Masateru Shiraki, Nobuaki Uesugi, Motonari Kume, Kazuhiko Kume, Shoen |
author_facet | Sakano, Daisuke Choi, Sungik Kataoka, Masateru Shiraki, Nobuaki Uesugi, Motonari Kume, Kazuhiko Kume, Shoen |
author_sort | Sakano, Daisuke |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4944721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-49447212016-07-22 Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass Sakano, Daisuke Choi, Sungik Kataoka, Masateru Shiraki, Nobuaki Uesugi, Motonari Kume, Kazuhiko Kume, Shoen Stem Cell Reports Article 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. Elsevier 2016-06-30 /pmc/articles/PMC4944721/ /pubmed/27373926 http://dx.doi.org/10.1016/j.stemcr.2016.05.015 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Sakano, Daisuke Choi, Sungik Kataoka, Masateru Shiraki, Nobuaki Uesugi, Motonari Kume, Kazuhiko Kume, Shoen Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass |
title | Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass |
title_full | Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass |
title_fullStr | Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass |
title_full_unstemmed | Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass |
title_short | Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass |
title_sort | dopamine d2 receptor-mediated regulation of pancreatic β cell mass |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944721/ https://www.ncbi.nlm.nih.gov/pubmed/27373926 http://dx.doi.org/10.1016/j.stemcr.2016.05.015 |
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