课题背景及目的
Monoamine transporters (MATs) are part of the solute carrier 6(SLC6) family of transporters. Expressed in both the central and peripheralnervous systems, they play a critical role inregulating neurotransmitter homeostasis.There are three types of MAT: thedopamine transporter (DAT; SLC6A3), the norepinephrine transporter(NET; SLC6A2), and the serotonin transporter (SERT; SLC6A4).Thesemediate the uptake of their respective transmitter from the extracellularspace intothe intracellular compartment. BecauseMATs play a pivotal role in controlling the signal amplitude and duration ofaction of monoaminergic neurotransmitters in the central nervous system (CNS)and peripheral nervous system (PNS) by altering their concentration in thesynaptic cleft(Lin et al., 2011; Ramamoorthy et al., 2011), modulation ofMATs markedly affects neuronal activity. A variety of MAT ligands are used astherapeutic agents and as tools for investigating neurobiological mechanismsof certain CNS disorders.
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MAT inhibitors are commonly used as tools for invitro and in vivo studies. Even after years of study, muchremains to be discovered concerning the mechanism of MAT-mediatedtransport, of MAT inhibition, and the structure of the MAT substrate anddrug binding sites. Notable studies, such as those defining the co-crystalstructures of the homologous bacterial and human serotonin transporter(hSERT) , have in recent years enhanced considerably the knowledge on thestructural biology of MATs. They have also been crucial in stimulatingstudies aimed at elucidating more fully the molecular mechanisms ofligand-MAT interactions and the transport process. Emphasis in theseexperiments are placed on defining the structural characteristics of thesetransporters and their functional mechanisms. Cocaine is one of the mostwidely abused psychostimulants. Although cocaine is a nonselectiveinhibitor of DAT, NET, and SERT, its reinforcing and rewarding effects aremediated primarily by inhibiting DA uptake by blocking the DA binding siteof DAT, thereby increasingperisynaptic DA levels. Efforts are ongoing to develop cocainebinding site antagonists that can competitively or noncompetitively preventit from binding to DAT without itself causing the stimulatory effects ofcocaine. |
Wewill perform functional dopamine uptake assays and substituted cysteinescanning accessibility methods (SCAM) and biotinylation experiments tocharacterize the interaction of the two modulators with the allosteric site.Ultimately we hope these studies will lead to the development of more uniquecompounds with promising potential to treat drug addiction.
课题背景及目的
Monoamine transporters (MATs) are part of the solute carrier 6(SLC6) family of transporters. Expressed in both the central and peripheralnervous systems, they play a critical role inregulating neurotransmitter homeostasis.There are three types of MAT: thedopamine transporter (DAT; SLC6A3), the norepinephrine transporter(NET; SLC6A2), and the serotonin transporter (SERT; SLC6A4).Thesemediate the uptake of their respective transmitter from the extracellularspace intothe intracellular compartment. BecauseMATs play a pivotal role in controlling the signal amplitude and duration ofaction of monoaminergic neurotransmitters in the central nervous system (CNS)and peripheral nervous system (PNS) by altering their concentration in thesynaptic cleft(Lin et al., 2011; Ramamoorthy et al., 2011), modulation ofMATs markedly affects neuronal activity. A variety of MAT ligands are used astherapeutic agents and as tools for investigating neurobiological mechanismsof certain CNS disorders.
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