Dopamine Negatively Regulates Insulin Secretion Through Activation of D1-D2 Receptor Heteromer

There is increasing evidence that dopamine (DA) functions as a negative regulator of glucose-stimulated insulin secretion; 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. Coexpression 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.

Automated summary

There is growing evidence that dopamine functions as a negative regulator of insulin secretion, but the underlying molecular mechanism remains unknown. This study found that D1 receptors play a role in the DA-mediated inhibition of insulin secretion, while overexpression of D2 receptors has a toxic effect on beta-cells. D1 and D2 receptors form heteromers in beta-cells, and D1 protects beta-cells from the harmful effects of DA by modulating D2 signaling.