Journal article
Enhancing glutamate transport: Mechanism of action of Parawixin1, a neuroprotective compound from Parawixia bistriata spider venom
Molecular pharmacology, v 72(5), pp 1228-1237
01 Nov 2007
PMID: 17646426
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Enhancing glutamate transport: Mechanism of action of Parawixin1, a neuroprotective compound from Parawixia bistriata spider venom
- Creators
- Andreia Cristina - University of PittsburghKarklin Fontana - University of PittsburghRene de Oliveira Beleboni - University of Sao PauloMarcin Wlodzimierz Wojewodzic - University of OsloWagner Ferreira dos Santos - University of Sao PauloJoaquim Coutinho-Netto - University of Sao PauloNina Julie Grutle - University of OsloSpencer D. Watts - University of PittsburghNiels Christian Danbolt - University of OsloSusan G. Amara - University of PittsburghAndreia C K Mortensen - Pharmacology and Physiology
- Publication Details
- Molecular pharmacology, v 72(5), pp 1228-1237
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Number of pages
- 10
- Grant note
- NS33272 / NINDS NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) MH080726 / NIMH NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) R01MH080726 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000250385300016
- Scopus ID
- 2-s2.0-35548981009
- Other Identifier
- 991020100088504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy