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• W2138832010 endingPage "1237" @default.
• W2138832010 startingPage "1228" @default.
• W2138832010 abstract "Previous studies have shown that a compound purified from the spider Parawixia bistriata venom stimulates the activity of glial glutamate transporters and can protect retinal tissue from ischemic damage. To understand the mechanism by which this compound enhances transport, we examined its effects on the functional properties of glutamate transporters after solubilization and reconstitution in liposomes and in transfected COS-7 cells. Here, we demonstrate in both systems that Parawixin1 promotes a direct and selective enhancement of glutamate influx by the EAAT2 transporter subtype through a mechanism that does not alter the apparent affinities for the cosubstrates glutamate or sodium. In liposomes, we observed maximal enhancement by Parawixin1 when extracellular sodium and intracellular potassium concentrations are within physiological ranges. Moreover, the compound does not enhance the reverse transport of glutamate under ionic conditions that favor efflux, when extracellular potassium is elevated and the sodium gradient is reduced, nor does it alter the exchange of glutamate in the absence of internal potassium. These observations suggest that Parawixin1 facilitates the reorientation of the potassium-bound transporter, the rate-limiting step in the transport cycle, a conclusion further supported by experiments showing that Parawixin1 does not stimulate uptake by an EAAT2 transport mutant (E405D) defective in the potassium-dependent reorientation step. Thus, Parawixin1 enhances transport through a novel mechanism targeting a step in the transport cycle distinct from substrate influx or efflux and provides a basis for the design of new drugs that act allosterically on transporters to increase glutamate clearance." @default.
• W2138832010 created "2016-06-24" @default.
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• W2138832010 date "2007-07-23" @default.
• W2138832010 modified "2023-10-18" @default.
• W2138832010 title "Enhancing Glutamate Transport: Mechanism of Action of Parawixin1, a Neuroprotective Compound from <i>Parawixia bistriata</i> Spider Venom" @default.
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• W2138832010 doi "https://doi.org/10.1124/mol.107.037127" @default.
• W2138832010 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17646426" @default.
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