American Diabetes Association
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Dopamine negatively regulates insulin secretion through activation of D1-D2 receptor heteromer

posted on 2022-06-22, 00:10 authored by Fumiya Uefune, Toru Aonishi, Tetsuya Kitaguchi, Harumi Takahashi, Susumu Seino, Daisuke Sakano, Shoen Kume


There is increasing evidence that dopamine (DA) functions as a negative regulator of glucose-stimulated insulin secretion (GSIS); however, the underlying molecular mechanism remains unknown. Using total internal reflection fluorescence microscopy, we monitored insulin granule exocytosis in primary islet cells to dissect the effect of DA. We found that D1 receptor antagonists rescued the DA-mediated inhibition of glucose-stimulated calcium (Ca2+) flux, thereby suggesting a role of D1 in the DA-mediated inhibition of insulin secretion. Overexpression of D2 but not D1 alone exerted an inhibitory and toxic effect that abolished the glucose-stimulated Ca2+ influx and insulin secretion in beta-cells. Proximity ligation and western blot assays revealed that D1 and D2 form heteromers in beta-cells. Treatment with a D1-D2 heteromer agonist, SKF83959, transiently inhibited glucose-induced Ca2+ influx and insulin granule exocytosis. Co-expression of D1 and D2 enabled beta-cells to bypass the toxic effect of D2 overexpression. DA transiently inhibited glucose-stimulated Ca2+ flux and insulin exocytosis by activating the D1-D2 heteromer. We conclude that D1 protects beta-cells from the harmful effects of DA by modulating D2 signaling. The finding will contribute to our understanding of the DA signaling in regulating insulin secretion and improve methods for preventing and treating diabetes.


This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#21H02978 to SK and #20K08325 to DS). This work was also supported in part by the Takeda Science Foundation, Japan Insulin Dependent Diabetes Mellitus (IDDM) Network


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