Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors
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Published:2021-02-16
Issue:1
Volume:11
Page:
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ISSN:2158-3188
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Container-title:Translational Psychiatry
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language:en
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Short-container-title:Transl Psychiatry
Author:
Aslanoglou Despoina, Bertera SuzanneORCID, Sánchez-Soto Marta, Benjamin Free R.ORCID, Lee Jeongkyung, Zong Wei, Xue Xiangning, Shrestha Shristi, Brissova Marcela, Logan Ryan W., Wollheim Claes B., Trucco Massimo, Yechoor Vijay K., Sibley David R.ORCID, Bottino Rita, Freyberg ZacharyORCID
Abstract
AbstractDopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α2A-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D2-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.
Funder
U.S. Department of Defense Pittsburgh Foundation U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke U.S. Department of Veterans Affairs U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
Publisher
Springer Science and Business Media LLC
Subject
Biological Psychiatry,Cellular and Molecular Neuroscience,Psychiatry and Mental health
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