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

doi:10.1016/j.isci.2022.104771

Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine

iScience. 2022 Jul 19;25(8):104771. doi: 10.1016/j.isci.2022.104771. eCollection 2022 Aug 19.

Authors

Despoina Aslanoglou¹, Suzanne Bertera², Laura Friggeri³, Marta Sánchez-Soto⁴, Jeongkyung Lee⁵, Xiangning Xue⁶, Ryan W Logan⁷, J Robert Lane^{8

9}, Vijay K Yechoor⁵, Peter J McCormick¹⁰, Jens Meiler^{3

11}, R Benjamin Free⁴, David R Sibley⁴, Rita Bottino^{2

12}, Zachary Freyberg^{1

13}

Affiliations

¹ Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
² Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, USA.
³ Department of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN, USA.
⁴ Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁵ Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
⁸ Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
⁹ Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Nottingham, UK.
¹⁰ Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
¹¹ Institute for Drug Discovery, Leipzig University Medical School, Leipzig, Germany.
¹² Imagine Pharma, Pittsburgh, PA, USA.
¹³ Department of Cell Biology, University of Pittsburgh, PA, USA.

Abstract

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 α_2A-adrenergic receptor (α_2A-AR) to reduce glucose-stimulated insulin secretion (GSIS). Moreover, in α-cells, bromocriptine acts via D2R to reduce glucagon secretion. α_2A-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 α_2A-AR versus D2R, providing a structural basis for bromocriptine's dual actions on β-cell α_2A-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.

Keywords: Chemistry; Endocrinology; biological sciences; molecular biology.

Abstract

Grants and funding