Phosphatase-Dependent Regulation of Dopamine D3 Receptor-Adenylyl Cyclase Complexes

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Dopamine is an important chemical of the brain. In the brain, dopamine controls several functions such as movement, memory, decision making and pleasure. These functions are made possible because dopamine attaches to specialized proteins called receptors. The receptors for dopamine are located on the cell's exterior. Five dopamine receptors named D1, D2, D3, D4 and D5 have been identified. Our preliminary studies suggest that the attachment of dopamine to D3 selectively promotes the interaction with another protein in cell's exterior called adenylyl cyclase 5 (a.k.a. AC5). As studies hint for a role of D3 and AC5 in the modulation of brain behaviors, we aim with NSERC monies to elucidate the biochemical mechanisms by which D3 and AC5 work together in the brain. We will explore how two biochemical reactions called phosphorylation (a process that adds phosphate to proteins) and dephosphorylation (a process that removes phosphate from proteins) control the crosstalk between D3 and AC5. Preliminary work done in our laboratory suggests a dephosphorylation of D3 following the attachment of dopamine to D3. The D3 dephophorylation is intimately related to the presence of AC5. Our hypothesis is that AC5 serves as a hub for phosphatases. Phosphatases are specialized enzymes performing dephosphorylation (removing phosphate) of proteins. Our initial experiments hint also for a role of D3 dephosphorylation in triggering the separation of D3 from AC5. The separation of D3 from AC5 turns on biochemical reactions inside the cells. We propose to identify the phosphatases controlled by AC5 that act on D3 dephophorylation and to uncover the molecular mechanisms involved in the crosstalk between D3 and AC5. The research will be done using cells and neurons growing in plastic dishes, recombinant DNA techniques and biochemical assays. We believe that the mechanistic information that will be gained with this NSERC-funded research will facilitate the design of tools to target specifically the D3 and AC5 duet. We trust these tools will be helpful to understand how brain behaviors are controlled by the concerted actions of D3 and AC5.