Dopamine’s Role in Transcription and Cell Proliferation

The dopamine D2 receptor has a previously unobserved role in modulating Wnt expression, according to a study published today in Scientific Reports. The new research could have impact the development of new therapeutics across multiple disciplines including nephrology, endocrinology, and psychiatry.

Dopamine is traditionally studied in the central nervous system; however, it has been increasingly implicated in the functions of other organs. This new study identifies a role of dopamine signaling via the D2 receptor outside the brain—in controlling signaling through the Wnt/β-catenin pathway, in part, through its effects on expression of Wnt3a, a key Wnt receptor ligand.

Both dopamine and the Wnt/β-catenin signaling pathways are ubiquitous across organ systems and species. Wnt signaling is essential for development and cell proliferation and is associated with a number of diseases from cancer to schizophrenia. However, little is known about the underlying mechanism regulating expression of Wnt3a or the modulation of its activity.

“In our research, we found that the dopamine D2 receptor is a transcriptional regulator of Wnt signaling and this ability to modulate Wnt signaling is important for better understanding development of hypertension,” says co–first author Prasad Konkalmatt of George Washington University.

The researchers focused on signaling in the kidneys and in the pancreas. More broadly, they found that dopamine receptors can act as regulators of gene transcription and that this signaling is important in controlling cell proliferation under healthy and disease conditions.

Investigators were surprised by how well conserved this dopamine regulation was across species and organs. They also found that lithium, one of the most commonly used psychiatric medications today, strongly increases the expression of D2 receptors, suggesting a new mechanism of action for this drug.

“Our work opens the door to a new way of thinking about dopamine signaling and its regulation,” says co–senior author Zachary Freyberg of the University of Pittsburgh. “By providing a new mechanism for the actions of lithium, we can better understand how this medication works and make better medications in the future to treat bipolar disorder and to improve the lives of the millions of people living with this illness.”

The investigators also discovered that a number of common gene polymorphisms associated with hypertension and renal injury control D2 receptor expression in renal cells. This discovery provides new mechanisms and drug discovery targets for hypertension and renal injury.