Neurotransmitter transporters in schistosomes: structure, function and prospects for drug discovery.
Neurotransmitter transporters (NTTs) play a fundamental role in the control of neurotransmitter signaling and homeostasis. Sodium symporters of the plasma membrane mediate the cellular uptake of neurotransmitter from the synaptic cleft, whereas proton-driven vesicular transporters sequester the neurotransmitter into synaptic vesicles for subsequent release. Together these transporters control how much transmitter is released and how long it remains in the synaptic cleft, thereby regulating the intensity and duration of signaling. NTTs have been the subject of much research in mammals and there is growing interest in their activities among invertebrates as well. In this review we will focus our attention on NTTs of the parasitic flatworm Schistosoma mansoni. Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a devastating disease that afflicts over 200 million people worldwide. Schistosomes have a well-developed nervous system and a rich diversity of neurotransmitters, including many of the small-molecule ("classical") neurotransmitters that normally employ NTTs in their mechanism of signaling. Recent advances in schistosome genomics have unveiled numerous NTTs in this parasite, some of which have now been cloned and characterized in vitro. Moreover new genetic and pharmacological evidence suggests that NTTs are required for proper control of neuromuscular signaling and movement of the worm. Among these carriers are proteins that have been successfully targeted for drug discovery in other organisms, in particular sodium symporters for biogenic amine neurotransmitters such as serotonin and dopamine. Our goal in this chapter is to review the current status of research on schistosome NTTs, with emphasis on biogenic amine sodium symporters, and to evaluate their potential for anti-schistosomal drug targeting. Through this discussion we hope to draw attention to this important superfamily of parasite proteins and to identify new directions for future research.
['Ribeiro|Paula|P|', 'Patocka|Nicholas|N|']
D000818:Animals D001679:Biogenic Amines D016000:Cluster Analysis D050483:Dopamine Plasma Membrane Transport Proteins D055808:Drug Discovery D023281:Genomics D015801:Helminth Proteins D006706:Homeostasis D006801:Humans D018377:Neurotransmitter Agents D050479:Neurotransmitter Transport Proteins D034622:RNA Interference D012550:Schistosoma mansoni D012555:Schistosomiasis mansoni D050486:Serotonin Plasma Membrane Transport Proteins D015398:Signal Transduction
Neurotransmitter neurotransmitter transporter Neurotransmitter transporter (NTT) NTT Schistosoma Biogenic amines CNS DAT Dopamine transporter (DAT) GABA GAT GLT Helminth NAT OAT PZQ RNA interference RNA interference (RNAi) RNAi SERT SLC SSRI Serotonin transporter (SERT) VMAT central nervous system dopamine transporter gamma-aminobutyric acid gamma-aminobutyric acid (GABA) transporter glutamate transporter iDAT invertebrate dopamine transporter noradrenaline transporter octopamine/tyramine transporter praziquantel selective serotonin reuptake inhibitor serotonin transporter short interfering RNA siRNA solute carrier vesicular monoamine transporter