Na?-dependent neurotransmitter transporters of the presynaptic plasma membrane function in the reuptake of neurotransmitters from the synaptic cleft. These proteins include the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT). They regulate the neurotransmission process by directly reducing the neurotransmitter concentration at the synaptic cleft. These transporter proteins can be inhibited by various drugs and therefore are the primary targets for: antidepressants such as fluoxetine (Prozac), sertraline (Zoloft), methylphenidate (Ritalin) -a prescription drug commonly used to treat attention-deficit hyperactivity disorder (ADHD), and psychostimulants like cocaine. In spite of their obvious pharmacological and clinical importance, the binding site for these drugs in the SERT, NET or DAT proteins are unknown, thereby hindering both the understanding of their inhibition mechanism and structure-based drug design.
We aim to identify the binding site in the human neurotransmitter transporters for these various types of drugs and psychostimulants, and to understand their inhibition mechanism, using a combination of structural, biochemical and pharmacological techniques. Specifically, we propose: (A) to propose to identify the binding site in the human SERT and NET proteins for three types of antidepressants;(B) to identify the binding site in DAT for cocaine;(C) to identify the binding sites in the human DAT protein for methylphenidate;(D) to characterize the molecular mechanism of inhibition of neurotransmitter transporters by these drugs.
We aim to understand the inhibition mechanisms of the serotonin and norepinephrine transporters by antidepressants and of the dopamine transporters by Ritalin and cocaine, using a combination of structural, biochemical and pharmacological approaches. Such information will aid in the design of more effective drugs for depression and for attention-deficit hyperactivity disorder, and of agents for the management of cocaine abuse.
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| Reith, Maarten E A; Blough, Bruce E; Hong, Weimin C et al. (2015) Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend 147:1-19 |
| Karpowich, Nathan K; Song, Jin Mei; Cocco, Nicolette et al. (2015) ATP binding drives substrate capture in an ECF transporter by a release-and-catch mechanism. Nat Struct Mol Biol 22:565-71 |
| Mulligan, Christopher; Fitzgerald, Gabriel A; Wang, Da-Neng et al. (2014) Functional characterization of a Na+-dependent dicarboxylate transporter from Vibrio cholerae. J Gen Physiol 143:745-59 |
| Ng, Joanne; Zhen, Juan; Meyer, Esther et al. (2014) Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood. Brain 137:1107-19 |
| Schmitt, Kyle C; Rothman, Richard B; Reith, Maarten E A (2013) Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates. J Pharmacol Exp Ther 346:2-10 |
| Waight, Andrew B; Czyzewski, Bryan K; Wang, Da-Neng (2013) Ion selectivity and gating mechanisms of FNT channels. Curr Opin Struct Biol 23:499-506 |
| Karpowich, Nathan K; Wang, Da-Neng (2013) Assembly and mechanism of a group II ECF transporter. Proc Natl Acad Sci U S A 110:2534-9 |
| Loew, Leslie M; Wang, Da-Neng (2013) Science communication: Quality at stake. Science 342:1169 |
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