期刊
JOURNAL OF NEUROCHEMISTRY
卷 112, 期 2, 页码 340-355出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2009.06474.x
关键词
carrier-mediated release; clinical therapeutics; drug targets; neurotransmitter transporters; reverse operation; transporter-mediated release
资金
- Austrian Science fund/FWF [P18706, SFB35]
- NIH [P41 RR-01081]
- NATIONAL CENTER FOR RESEARCH RESOURCES [P41RR001081] Funding Source: NIH RePORTER
Sodium-chloride coupled neurotransmitter transporters achieve reuptake of their physiological substrate by exploiting the pre-existing sodium-gradient across the cellular membrane. This terminates the action of previously released substrate in the synaptic cleft. However, a change of the transmembrane ionic gradients or specific binding of some psychostimulant drugs to these proteins, like amphetamine and its derivatives, induce reverse operation of neurotransmitter:sodium symporters. This effect eventually leads to an increase in the synaptic concentration of non-exocytotically released neurotransmitters [and - in the case of the norepinephrine transporters, underlies the well-known indirect sympathomimetic activity]. While this action has long been appreciated, the underlying mechanistic details have been surprisingly difficult to understand. Some aspects can be resolved by incorporating insights into the oligomeric nature of transporters, into the nature of the accompanying ion fluxes, and changes in protein kinase activities.
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