文章基本信息

标题：Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine
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作者：Despoina Aslanoglou ; Suzanne Bertera ; Laura Friggeri 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：8
页码：1-29
DOI：10.1016/j.isci.2022.104771
语种：English
出版社：Elsevier
摘要：SummaryBromocriptine 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 D2receptors (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.Graphical abstractDisplay OmittedHighlights•In β-cells, bromocriptine acts on both D2R and α2A-AR to lower insulin secretion•In α-cells, bromocriptine acts via D2R to reduce glucagon secretion•Distinct G proteins are recruited to D2R versus α2A-AR in response to bromocriptine•Bromocriptine is a G protein-biased and partial agonist at α2A-ARChemistry; Biological sciences; Molecular biology; Endocrinology