Summary 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 exocytosis of insulin granules in primary islet cells to dissect the effect of DA. We found that D1 receptor antagonists rescued DA-mediated inhibition of glucose-stimulated calcium (Ca2+) flux, suggesting a role for D1 in DA-mediated inhibition of insulin secretion. Overexpression of D2, but not D1 alone, exerted an inhibitory and toxic effect that suppressed 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 heteromeric agonist, SKF83959, transiently inhibited glucose-induced Ca2+ influx and insulin granule exocytosis. Coexpression of D1 and D2 allowed beta cells to escape 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 deleterious effects of DA by modulating D2 signaling. The finding will contribute to our understanding of DA signaling in regulating insulin secretion and improve methods to prevent and treat diabetes. |
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Diabetes is a chronic, lifelong health condition caused by abnormalities in the production and use of the hormone insulin in the body . Research has shown that the feel-good hormone dopamine (DA) plays a key role in how the body regulates insulin production .
Insulin is typically secreted by cells in the pancreas called “beta cells ,” in response to glucose, a process aptly called “ glucose-stimulated insulin secretion ” (GSIS). Dopamine (DA) downregulates GSIS, leading to transient changes in the body’s insulin levels.But the mechanism behind this regulation was unknown, until now.
Recently, a team led by researchers at the Tokyo Institute of Technology (Tokyo Tech) discovered the precise mechanism by which DA regulates insulin secretions. Using a technique called "total internal reflection fluorescence microscopy ," they were able to reveal that DA "receptors" —proteins in cells to which DA can bind, called D1 and D2—act together to achieve transient regulation of insulin.
“We found that D1 receptor antagonists , drugs that block the activation of D1 receptors, decreased dopamine-mediated inhibition of insulin secretion. We also saw that overexpression of only D2 receptors in beta cells exerted an inhibitory and toxic effect and abolished insulin secretion in beta cells. This gave us a clue about the downregulation mechanism,” explains Professor Shoen Kume of Tokyo Tech, who led the study.
The research team then performed more experiments called "proximity ligation" and "Western blot assays" to further study the receptors. They discovered that D1 and D2 joined together to form a complex called a "heteromer" . When activated by DA, this heteromer transiently inhibits insulin secretion . They also saw that when D1 and D2 were simultaneously expressed in beta cells, the cells were able to escape the toxic effects of D2 overexpression.
Dr. Kume says, “From these findings, it can be concluded that D1 modulates D2 signaling to protect beta cells from the harmful effects of DA. "This study greatly improves our understanding of DA signaling in diabetes."
Understanding the mechanism of DA signaling in regulating insulin secretion will surely provide new therapeutic targets for the prevention, treatment and control of diabetes.
