STRUCTURAL & FUNCTIONAL STUDIES OF HUMAN VESICULAR NEUROTRANSMITTER TRANSPORTERS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The transmembrane transport of neurotransmitters is of fundamental importance for proper signaling between neurons. The transport processes are mediated by distinct classes of membrane transport proteins that have key roles in controlling the neurotransmitter concentration in the synaptic cleft. Overall, these transporters can be classed as intracellular vesicular transporters that are responsible for sequestering transmitters from the cytoplasm into synaptic vesicles, and plasma membrane transporters that are responsible for sequestering released transmitter from the extracellular space. There are three subclasses of intracellular transporters: the vesicular amine transporters (SLC18), the vesicular inhibitory amino acid transporter family (SLC32) and the vesicular glutamate transporters (SLC17). There are two major subclasses of plasma membrane transporter: the high-affinity glutamate transporters and the Na+Cl -coupled transporters. The latter subclass is the largest and includes transporters of dopamine, norepinephrine, glycine and GABA. The main research objective is to improve our understanding of the human vesicular neurotransmitter transporters, by utilizing structural data to perform functional studies. Homology modeling could then be used to produce high-quality structural models for proteins from the same family, allowing us to plan specific functional studies on each member, and possibly enabling the design of small molecules that fit the specific targets (drug design).