New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion

Zachary J. Farino, Travis J. Morgenstern, Antonella Maffei, Matthias Quick, Alain J. De Solis, Pattama Wiriyasermkul, Robin J. Freyberg, Despoina Aslanoglou, Denise Sorisio, Benjamin P. Inbar, R. Benjamin Free, Prashant Donthamsetti, Eugene V. Mosharov, Christoph Kellendonk, Gary J. Schwartz, David R. Sibley, Claudia Schmauss, Lori M. Zeltser, Holly Moore, Paul E. Harris & 2 others Jonathan A. Javitch, Zachary Freyberg

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Although long-studied in the central nervous system, there is increasing evidence that dopamine (DA) has important roles in the periphery including in metabolic regulation. Insulin-secreting pancreatic β-cells express the machinery for DA synthesis and catabolism, as well as all five DA receptors. In these cells, DA functions as a negative regulator of glucose-stimulated insulin secretion (GSIS), which is mediated by DA D2-like receptors including D2 (D2R) and D3 (D3R) receptors. However, the fundamental mechanisms of DA synthesis, storage, release, and signaling in pancreatic β-cells and their functional relevance in vivo remain poorly understood. Here, we assessed the roles of the DA precursor l-DOPA in β-cell DA synthesis and release in conjunction with the signaling mechanisms underlying DA’s inhibition of GSIS. Our results show that the uptake of l-DOPA is essential for establishing intracellular DA stores in β-cells. Glucose stimulation significantly enhances l-DOPA uptake, leading to increased DA release and GSIS reduction in an autocrine/paracrine manner. Furthermore, D2R and D3R act in combination to mediate dopaminergic inhibition of GSIS. Transgenic knockout mice in which β-cell D2R or D3R expression is eliminated exhibit diminished DA secretion during glucose stimulation, suggesting a new mechanism where D2-like receptors modify DA release to modulate GSIS. Lastly, β-cell-selective D2R knockout mice exhibit marked postprandial hyperinsulinemia in vivo. These results reveal that peripheral D2R and D3R receptors play important roles in metabolism through their inhibitory effects on GSIS. This opens the possibility that blockade of peripheral D2-like receptors by drugs including antipsychotic medications may significantly contribute to the metabolic disturbances observed clinically.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Jan 1 2019

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Dopamine D3 Receptors
Dopamine D2 Receptors
Insulin-Secreting Cells
Dopamine
Insulin
Glucose
Dopamine Receptors
Knockout Mice
Drug Receptors
Hyperinsulinism
Transgenic Mice
Antipsychotic Agents
Central Nervous System

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Farino, Z. J., Morgenstern, T. J., Maffei, A., Quick, M., De Solis, A. J., Wiriyasermkul, P., ... Freyberg, Z. (Accepted/In press). New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion. Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0344-6

New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion. / Farino, Zachary J.; Morgenstern, Travis J.; Maffei, Antonella; Quick, Matthias; De Solis, Alain J.; Wiriyasermkul, Pattama; Freyberg, Robin J.; Aslanoglou, Despoina; Sorisio, Denise; Inbar, Benjamin P.; Free, R. Benjamin; Donthamsetti, Prashant; Mosharov, Eugene V.; Kellendonk, Christoph; Schwartz, Gary J.; Sibley, David R.; Schmauss, Claudia; Zeltser, Lori M.; Moore, Holly; Harris, Paul E.; Javitch, Jonathan A.; Freyberg, Zachary.

In: Molecular Psychiatry, 01.01.2019.

Research output: Contribution to journalArticle

Farino, ZJ, Morgenstern, TJ, Maffei, A, Quick, M, De Solis, AJ, Wiriyasermkul, P, Freyberg, RJ, Aslanoglou, D, Sorisio, D, Inbar, BP, Free, RB, Donthamsetti, P, Mosharov, EV, Kellendonk, C, Schwartz, GJ, Sibley, DR, Schmauss, C, Zeltser, LM, Moore, H, Harris, PE, Javitch, JA & Freyberg, Z 2019, 'New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion', Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0344-6
Farino ZJ, Morgenstern TJ, Maffei A, Quick M, De Solis AJ, Wiriyasermkul P et al. New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion. Molecular Psychiatry. 2019 Jan 1. https://doi.org/10.1038/s41380-018-0344-6
Farino, Zachary J. ; Morgenstern, Travis J. ; Maffei, Antonella ; Quick, Matthias ; De Solis, Alain J. ; Wiriyasermkul, Pattama ; Freyberg, Robin J. ; Aslanoglou, Despoina ; Sorisio, Denise ; Inbar, Benjamin P. ; Free, R. Benjamin ; Donthamsetti, Prashant ; Mosharov, Eugene V. ; Kellendonk, Christoph ; Schwartz, Gary J. ; Sibley, David R. ; Schmauss, Claudia ; Zeltser, Lori M. ; Moore, Holly ; Harris, Paul E. ; Javitch, Jonathan A. ; Freyberg, Zachary. / New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion. In: Molecular Psychiatry. 2019.
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AU - De Solis, Alain J.

AU - Wiriyasermkul, Pattama

AU - Freyberg, Robin J.

AU - Aslanoglou, Despoina

AU - Sorisio, Denise

AU - Inbar, Benjamin P.

AU - Free, R. Benjamin

AU - Donthamsetti, Prashant

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AU - Zeltser, Lori M.

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