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Los mecanismos de conducción de aniones por transportadores acoplados de glutamato

Jan-Philipp Machtens¹, Daniel Kortzak², Christine Lansche²

¹Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, 52428 Jülich, Germany; Institut für Neurophysiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany; Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.

|January 31, 2015

Resumen

Los transportadores de aminoácidos excitatorios (EAAT) funcionan como canales iónicos. Su movimiento abre una vía aniónica, regulando la excitabilidad neuronal y impactando potencialmente en trastornos neurológicos como la epilepsia.

Área de la Ciencia:

La neurociencia es la neurociencia.
Biología Molecular Biología Molecular
La biofísica es la biofísica.

Sus antecedentes:

Los transportadores de aminoácidos excitatorios (EAAT) son cruciales para la eliminación del glutamato de las sinapsis.
Los EAAT funcionan no solo como transportadores, sino también como canales selectivos de aniones.
Los canales aniónicos EAAT disfuncionales están vinculados a afecciones neurológicas como la ataxia y la epilepsia.

Objetivo del estudio:

Para aclarar el mecanismo por el cual los EAATs llevan a cabo aniones.
Investigar las bases estructurales del transporte aniónico en los EAAT.

Principales métodos:

Simulaciones de dinámica molecular del homólogo procariótico GltPh.Ph.
Espectroscopia de fluorescencia de GltPh con residuos de triptófano insertados.
Las grabaciones de la pinza de parche de EAAT de mamíferos (EAAT2/EAAT4).

Principales resultados:

Se identificaron estados no conductores de GltPh en conformaciones orientadas hacia afuera e interior.
Las vías selectivas de aniones se forman a través del movimiento lateral del dominio de transporte de glutamato en conformaciones intermedias.
Las mutaciones en los residuos formadores de poros afectaron tanto a las simulaciones de GltPh como a la actividad y selectividad del canal EAAT2/EAAT4.

Conclusiones:

Se propone un marco mecanicista para la conducción de aniones a través de transportadores de neurotransmisores.
Los EAAT pueden funcionar como canales iónicos ligandos, con el transporte de aniones vinculado a cambios conformacionales.
Comprender este mecanismo ofrece información sobre los trastornos neurológicos relacionados con la EAAT.

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