Room: Rm. 2452 RGN
Office: 613-562-5800 ext. 4848
Work E-mail: [email protected]
Senior Scientist, Neuroscience, Ottawa Hospital Research Institute
Division of Neurology-Neurosciences, Hospital
Associate Professor, Department of Medicine (Division of Neurology), cross-appointed to the Department of Cellular and Molecular Medicine and Department of Psychiatry, University of Ottawa
- Dopamine Receptors
- G Protein
- Signal Transduction
Major Research Activities
Research in our laboratory focuses on the elucidation of the molecular and regulatory mechanisms controlling the functionality of a class of proteins called receptors located on the cell surface and to which the brain chemical dopamine attaches and induces their activation. The dopamine receptors (D1R, D2R, D3R, D4R and D5R) are plasma membrane proteins sharing structural and functional similarities with one of the largest family of receptors found in living organisms. Indeed, dopamine receptors belong to the large family of G protein-coupled receptors or GPCRs. Impairment in dopamine receptor function is a feature of several neuropsychiatric disorders such as schizophrenia, Parkinson's disease, Huntington, depression and drug addiction. Administration of drugs modulating the activity of dopamine receptors are used to treat symptoms observed in neuropsychiatric disorders associated with defective dopamine neurotransmission.
GPCRs specializing in the recognition and attachment of dopamine instruct to cells specific chemical information through the recruitment of different effectors such as adenylyl cyclases (enzymes that synthesize a second messenger named cyclic AMP inside cells), ion channels and pumps (allowing cells to control the entry and exit of small charged molecules). The communication or cross-talk between dopamine receptors and its effectors is mediated by the stimulation of molecular switches known as heterotrimeric G proteins on which dopamine receptors initiate a repetitive exchange cycle between two guanosine nucleotides: guanosine diphosphate or GDP-bound G proteins (switch off)
guanosine triphosphate or GTP-bound G proteins (switch on). While dopamine receptors mediate their effects on cells through the classical regulation of G proteins, they can also control cell activity in a G protein-independent manner via direct protein-protein interactions with effectors and other intracellular partners. In cells, the extent of dopamine receptor activation is subjected to a dynamic regulation by intracellular enzymes called kinases and phosphatases. These enzymes catalyze on dopamine receptors and its signaling partners the addition (phosphorylation by kinases) and removal (dephosphorylation by phosphatases) of a cell chemical known as phosphate. A disruption in the interplay between kinases and phosphatases regulating dopamine receptors and its downstream partners has been implicated in brain diseases also linked to defects in dopamine neurotransmission. Our major endeavors employ recombinant DNA technologies, RNA interference, biochemical and cell biological approaches to probe the underlying molecular relationships between dopamine receptor structure, G protein and effector regulation, kinases, phosphatases and drug action. Future work will be aimed at using molecular genetic to understand in more detail the relevance of these molecular relationships in animal models. Knowledge gained from our studies may aid in the development of novel therapeutic strategies for neuropsychiatric disorders.
dopamine receptors, G protein, signal transduction, desensitization, phosphorylation, trafficking, Schizophrenia, Parkinson's Disease