Two brain proteins associated with distinct neural functions have been found to interact physically and functionally. While both can regulate nerve cell firing and are implicated in learning, one, a structural protein for the excitatory neurotransmitter glutamate, reduced the function of the other, a protein receptor for dopamine. The findings, published in the May 25 Journal of Biological Chemistry, reveal that the structural protein, PSD-95, may be an effective drug target for behavioral disorders associated with dopamine imbalances in the brain.
Though it has been known that the dendritic side of glutamate synapses contain copious dopamine receptors with profound modulatory effects, how the dopamine receptors are regulated within these synapses has remained unclear. Previously, Wei-Dong Yao, HMS assistant professor of psychiatry at the New England Primate Research Center (NEPRC), found that PSD-95 in glutamatergic synapses was involved in dopamine signaling. “Knockout mice without PSD-95 were more sensitive to psychostimulants that increase dopamine signaling than normal mice,” said Yao, who has shown PSD-95’s role in dopamine signaling through utilization of cocaine and amphetamines.
Now Yao, postdoctoral fellow Jingping Zhang, and colleagues report that D1 dopamine receptors and PSD-95 coprecipitated in vivo in such areas as the dopamine-rich striatum and cortex and in vitro in cell lines. Looking for a more detailed view of the proteins’ entanglement, the researchers found that the molecules linked together at PSD-95’s N-terminus and at the intracellular C-terminal tail of the D1 receptor.
“Here’s the novel thing,” Yao explained. “The interaction did not involve any of the well-characterized domains. Instead, it involved a novel protein domain of PSD-95.” The functional implications of the N-terminus domain are not known, but some hints of function are provided by the site of interaction on the D1 receptor.
The C-terminal tail of the D1 receptor is known for trafficking dopamine receptors to and from active duty at the cell membrane. When radioligand studies showed no dopamine-binding differences or differences in the total number of dopamine receptors with and without PSD-95 expression, Yao and his research team wondered whether the availability of active receptors at the cell surface explained the differences in dopamine signaling. Indeed, the scientists found through biochemical assays and confocal microscopy that PSD-95 lowered the levels of D1 receptors on the cell membrane.
The identification of PSD-95 as a molecule that balances two important neurotransmitter systems could have implications for a variety of psychiatric disorders, including schizophrenia and addiction. “In addition to drugs which act primarily as dopamine receptor agonists or antagonists,” said Gregory Miller, HMS assistant professor of psychiatry at NEPRC and a co-author on the paper, “PSD-95 now represents a new potential target for medications that modulate dopaminergic function.”
