Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine
Summary: Bromocriptine is approved as a diabetes therapy, yet its therapeutic mechanisms remain unclear. Though bromocriptine’s actions have been mainly attributed to the stimulation of brain dopamine D2 receptors (D2R), bromocriptine also targets the pancreas. Here, we employ bromocriptine as a too...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222010434 |
| _version_ | 1818490106814660608 |
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| author | Despoina Aslanoglou Suzanne Bertera Laura Friggeri Marta Sánchez-Soto Jeongkyung Lee Xiangning Xue Ryan W. Logan J. Robert Lane Vijay K. Yechoor Peter J. McCormick Jens Meiler R. Benjamin Free David R. Sibley Rita Bottino Zachary Freyberg |
| author_facet | Despoina Aslanoglou Suzanne Bertera Laura Friggeri Marta Sánchez-Soto Jeongkyung Lee Xiangning Xue Ryan W. Logan J. Robert Lane Vijay K. Yechoor Peter J. McCormick Jens Meiler R. Benjamin Free David R. Sibley Rita Bottino Zachary Freyberg |
| author_sort | Despoina Aslanoglou |
| collection | DOAJ |
| description | Summary: Bromocriptine is approved as a diabetes therapy, yet its therapeutic mechanisms remain unclear. Though bromocriptine’s actions have been mainly attributed to the stimulation of brain dopamine D2 receptors (D2R), bromocriptine also targets the pancreas. Here, we employ bromocriptine as a tool to elucidate the roles of catecholamine signaling in regulating pancreatic hormone secretion. In β-cells, bromocriptine acts on D2R and α2A-adrenergic receptor (α2A-AR) to reduce glucose-stimulated insulin secretion (GSIS). Moreover, in α-cells, bromocriptine acts via D2R to reduce glucagon secretion. α2A-AR activation by bromocriptine recruits an ensemble of G proteins with no β-arrestin2 recruitment. In contrast, D2R recruits G proteins and β-arrestin2 upon bromocriptine stimulation, demonstrating receptor-specific signaling. Docking studies reveal distinct bromocriptine binding to α2A-AR versus D2R, providing a structural basis for bromocriptine’s dual actions on β-cell α2A-AR and D2R. Together, joint dopaminergic and adrenergic receptor actions on α-cell and β-cell hormone release provide a new therapeutic mechanism to improve dysglycemia. |
| first_indexed | 2024-12-10T17:12:52Z |
| format | Article |
| id | doaj.art-073b353a30d149d4b39ba15b63d8a932 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-10T17:12:52Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-073b353a30d149d4b39ba15b63d8a9322022-12-22T01:40:15ZengElsevieriScience2589-00422022-08-01258104771Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptineDespoina Aslanoglou0Suzanne Bertera1Laura Friggeri2Marta Sánchez-Soto3Jeongkyung Lee4Xiangning Xue5Ryan W. Logan6J. Robert Lane7Vijay K. Yechoor8Peter J. McCormick9Jens Meiler10R. Benjamin Free11David R. Sibley12Rita Bottino13Zachary Freyberg14Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USAInstitute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, USADepartment of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN, USAMolecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USADiabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADepartment of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USADepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USADivision of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, UK; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Nottingham, UKDiabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USACentre for Endocrinology, William Harvey Research Institute, Bart’s and the London School of Medicine and Dentistry, Queen Mary, University of London, London, UKDepartment of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN, USA; Institute for Drug Discovery, Leipzig University Medical School, Leipzig, GermanyMolecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USAMolecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USAInstitute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, USA; Imagine Pharma, Pittsburgh, PA, USATranslational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Cell Biology, University of Pittsburgh, PA, USA; Corresponding authorSummary: Bromocriptine is approved as a diabetes therapy, yet its therapeutic mechanisms remain unclear. Though bromocriptine’s actions have been mainly attributed to the stimulation of brain dopamine D2 receptors (D2R), bromocriptine also targets the pancreas. Here, we employ bromocriptine as a tool to elucidate the roles of catecholamine signaling in regulating pancreatic hormone secretion. In β-cells, bromocriptine acts on D2R and α2A-adrenergic receptor (α2A-AR) to reduce glucose-stimulated insulin secretion (GSIS). Moreover, in α-cells, bromocriptine acts via D2R to reduce glucagon secretion. α2A-AR activation by bromocriptine recruits an ensemble of G proteins with no β-arrestin2 recruitment. In contrast, D2R recruits G proteins and β-arrestin2 upon bromocriptine stimulation, demonstrating receptor-specific signaling. Docking studies reveal distinct bromocriptine binding to α2A-AR versus D2R, providing a structural basis for bromocriptine’s dual actions on β-cell α2A-AR and D2R. Together, joint dopaminergic and adrenergic receptor actions on α-cell and β-cell hormone release provide a new therapeutic mechanism to improve dysglycemia.http://www.sciencedirect.com/science/article/pii/S2589004222010434Chemistrybiological sciencesmolecular biologyEndocrinology |
| spellingShingle | Despoina Aslanoglou Suzanne Bertera Laura Friggeri Marta Sánchez-Soto Jeongkyung Lee Xiangning Xue Ryan W. Logan J. Robert Lane Vijay K. Yechoor Peter J. McCormick Jens Meiler R. Benjamin Free David R. Sibley Rita Bottino Zachary Freyberg Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine iScience Chemistry biological sciences molecular biology Endocrinology |
| title | Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine |
| title_full | Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine |
| title_fullStr | Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine |
| title_full_unstemmed | Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine |
| title_short | Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine |
| title_sort | dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine |
| topic | Chemistry biological sciences molecular biology Endocrinology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222010434 |
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