Neurons communicate to other cells through the actions of neurotransmitter molecules acting on receptor proteins. Transmitters are stored in synaptic vesicles and released via a calcium-dependent mechanism involving several protein-interactions and the fusion of synaptic vesicles with the plasma membrane. Synaptic vesicles are then retrieved from the plasma membrane and quickly refilled with transmitter molecules to maintain an efficient cycle of neurotransmission. While the molecular details of transmitter release and vesicle retrieval have been the subject of intense investigation, almost no information is available regarding the molecular basis of the vesicular refilling process. Dr. Torres' research program has focused on the functional regulation of the dopamine transporter (DAT). Preliminary data from the Dr. Torres' laboratory demonstrate a direct interaction between DAT and the synaptic proteins SNAP-25 and synaptogyrin-3. SNAP-25 is one of the SNARE proteins involved in synaptic vesicle docking and fusion whereas synaptogyrin-3 is a transmembrane synaptic vesicle protein. The association of DAT with a SNARE protein and a synaptic vesicle protein could provide the molecular basis for a physical and functional coupling between the plasma membrane DA re-uptake system and synaptic vesicles for subsequent vesicular uptake. Thus, a physical and functional coupling between DAT and synaptic vesicles would ensure a rapid and efficient mechanism for re-filling vesicles with DA after neurotransmitter release. Therefore, to explore this hypothesis, Dr. Torres will examine the physiological significance of DAT protein-protein interactions with the synaptic proteins SNAP-25 and synaptogyrin-3. The following aims will be pursued: Aim 1 will examine the molecular determinants involved in DAT interactions with SNAP-25 and synaptogyrin-3 and the specificity of these interactions. Aim 2 will examine the functional consequences of disrupting these interactions on DAT function and vesicular DA storage. Aim 3 will test the hypothesis that manipulations that alter vesicular DA storage also have an effect on DAT function and DAT interactions with SNAP-25 and synaptogyrin-3. Aim 4 will test the hypothesis that DAT interacts physically and functionally with synaptic vesicles.
This research will not only increase the understanding of synaptic transmission and molecular mechanisms associated with synaptic vesicular refilling, but will also provide undergraduate and graduate students with research opportunities in neuroscience. Dr. Torres is an Assistant Professor in the Department of Neurobiology at the University of Pittsburgh since July 1, 2004. During the past year, he has been nominated to the Minority Education Training Professional Advancement Committee (METPAC) from the Society for Neuroscience and to the Committee on Minorities from the American Society of Pharmacology and Experimental Therapeutics (ASPET), where he is currently the Chair of the committee. In addition, Dr. Torres oversees minority recruitment to the Center for Neuroscience graduate program at the University of Pittsburgh. It is the aspiration and interest Dr. Torres to use these positions and connections to actively recruit and lead young, aspiring, and especially minority researchers to be involved in the proposed work.
