Protein Links Dopamine and Depression

Mouse Study Suggests Alternate Approaches to Therapy

The neurotransmitter dopamine is responsible for carrying out subtle functions such as motor control, motivation, response to reward, and mood. Dopamine is a single message, yet somehow is translated into many different actions, and miscommunication can lead to several neurodegenerative diseases and psychiatric disorders. To solve any of these problems, targeting the message is not enough; researchers must understand the details of how that message is translated. A study from the laboratory of Li-Huei Tsai, published in the July 29 Cell, uncovers a molecule that helps regulate how neurons respond to dopamine’s signal. The protein, Par-4, also provides a surprising connection between dopamine communication and depression in an animal model.

Photo by Steve Gilbert Li-Huei Tsai (right) and Sang Ki Park found a molecular pathway that they hope will spark new interest in dopamine’s role in depression.

Mixed Messages
Dopamine’s message is received by two main classes of dopamine receptor in the brain, D1 and D2. The two perform a kind of yin and yang balancing act to control a neuron’s response. When the D1 receptor is bound by dopamine, it stimulates the cell by activating the enzyme adenylate cyclase and the signaling molecule cyclic AMP to turn on gene transcription. D2 receptors, however, have the opposite effect, inhibiting cyclic AMP production and preventing cell activation. By working against each other, the receptors achieve a balance between activation and inhibition, serving as a homeostatic mechanism for dopamine’s effects on the cell.

Tsai, Howard Hughes investigator and HMS professor of pathology, said that this simple system looks a little too simple compared to the intricacies of other known cellular signaling pathways. The receptors must have many complex interactions with other proteins that carry out dopamine’s many functions. Tsai’s team, led by postdoctoral fellow Sang Ki Park, chose to tackle the D2 receptor, which is less well characterized. Impairment of the D2 receptor has been found in mood disorders, drug addiction, and schizophrenia (which is currently treated with D2 receptor antagonists).

The D2 receptor has a long intracellular loop that is thought to be a hub for interactions with other proteins. Park performed a screen for molecules that interact with the D2 receptor at this loop. Among the potential candidates he found, Park focused on Par-4, which had been studied for its role in cell death, but did not have a clear function in the brain. Park was interested in the protein because it binds to the same region on D2 that serves as a binding site for the signaling molecule calmodulin. Calmodulin orchestrates many of the changes that occur in response to calcium, a critical chemical signal in neurons.

Further studies showed that calmodulin and Par-4 compete for the same spot on the D2 receptor. In the absence of calcium, Par-4 wins the seat. “But when there’s any activity—stimulation, membrane depolarization, and so forth,” Tsai said, “there’s a rise in intracellular calcium levels, and then calmodulin can kick off Par-4 and bind to the D2 receptor instead.”

Calmodulin has been shown to inhibit normal functioning of the D2 receptor. Tsai and her colleagues believe that Par-4 may have the opposite effect: sustaining the D2 receptor’s function of inhibiting the activation of cells by dopamine. By competing with calmodulin, it may serve as a kind of buffer against extreme responses to calcium signals in the cell.

“Our study provides a very specific pathway downstream of dopamine that may lead to depression.”

To see how the molecule functions physiologically, the team was fortunate to find Par-4–deficient mice in the neighboring lab of Yang Shi, HMS professor of pathology. His team had noted no apparent anatomical deficits in the mice; Tsai’s team verified that there were no structural differences in the brain. But when they subjected the mice to some well-established behavioral tests, they found something striking. “We basically found that these animals are depressed,” Tsai said. In one common test for depressionlike symptoms, mice are placed in a clear cylinder of water with no possible exit. Normal mice will continue to swim even though they are trapped, but the Par-4–deficient animals readily gave up. In another test, food is placed in an open area, something that rodents typically avoid. The Par-4–deficient mice were much less willing to brave the open area in order to get food, even if they were mildly starved. Though no one can say for sure whether animal models truly capture the mechanisms of human depression, tests like these have become well-established models to test depression therapies.

Antonio Bonci, associate professor of neurology at the University of California, San Francisco, said that the findings are “very exciting, but still preliminary.” One potential implication of the paper, he said, is that Par-4 could yield some further insights about depression. Studies of the regions in the brain where Par-4 functions could help locate areas involved in depression, something that is not fully understood.

Tsai hopes that the study will generate interest in the possible role of dopamine in depression. Current treatments for depression target serotonin levels at synapses. An enduring puzzle is why they often take several weeks to begin working; this delay suggests that adaptations take place far downstream of the immediate effect on serotonin, including changes in other neurotransmitter systems. Though dopamine has not received the serious scrutiny in depression that serotonin has, some of the symptoms of depression, such as a loss of motivation and a loss of pleasure in activities, are functions governed by the reward and motivation circuits controlled by dopamine.

“Depression is a very complicated problem,” Tsai said. “Our study provides a very specific pathway downstream of dopamine that may lead to depression.” She believes that uncovering these downstream steps in dopamine communication may reveal more specific strategies for therapy.

—Courtney Humphries

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