Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine
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
Affiliations
Despoina Aslanoglou
Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
Suzanne Bertera
Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, USA
Laura Friggeri
Department of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN, USA
Marta Sánchez-Soto
Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Jeongkyung Lee
Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Xiangning Xue
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
Ryan W. Logan
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA
J. Robert Lane
Division 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, UK
Vijay K. Yechoor
Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Peter J. McCormick
Centre for Endocrinology, William Harvey Research Institute, Bart’s and the London School of Medicine and Dentistry, Queen Mary, University of London, London, UK
Jens Meiler
Department of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN, USA; Institute for Drug Discovery, Leipzig University Medical School, Leipzig, Germany
R. Benjamin Free
Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
David R. Sibley
Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Rita Bottino
Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, USA; Imagine Pharma, Pittsburgh, PA, USA
Zachary Freyberg
Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Cell Biology, University of Pittsburgh, PA, USA; Corresponding author
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.
