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Estructura y dinámica del receptor AMPA GluA2 en los estados de reposo, pre-abierto y desensibilizado

Katharina L Dürr¹, Lei Chen¹, Richard A Stein²

¹Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.

|August 12, 2014

Resumen

Este estudio revela las estructuras del receptor GluA2 AMPA en los estados de reposo, activación y desensibilización. Comprender estas conformaciones proporciona información sobre la neurotransmisión y el desarrollo de fármacos para trastornos neurológicos.

Área de la Ciencia:

La neurociencia es la neurociencia.
Biología Molecular Biología Molecular
Biología Estructural Biología estructural.

Sus antecedentes:

Los receptores ionotrópicos del glutamato (iGluR) son cruciales para la neurotransmisión excitatoria rápida.
Existe información estructural y dinámica limitada para iGluRs intactos en varios estados funcionales.

Objetivo del estudio:

Esclarecer las estructuras y la dinámica del receptor GluA2 AMPA intacto en estados de reposo, activación y desensibilización.
Comprender los cambios conformacionales asociados con la unión, activación y desensibilización del agonista.

Principales métodos:

Microscopía cryoelectrónica (cryo-EM) para la determinación estructural.
Experimentos de resonancia doble electrón-electrón (DEER) en mutantes de cisteína para sondear la dinámica conformacional.

Principales resultados:

Determinadas estructuras del receptor GluA2 AMPA en estados de reposo apo, activado (con agonistas parciales y un modulador alostérico positivo) y desensibilizado (con fluorowilliardiina).
Se demostró cómo la unión agonista altera la conformación del dominio de unión al ligando.
Reveló grandes reordenamientos conformacionales en los dominios amino-terminales y de unión de ligandos durante la desensibilización.

Conclusiones:

Principios mecanicistas establecidos para el antagonismo, la activación y la desensibilización de AMPA iGluR.
Proporciona una base estructural para comprender la función y la modulación de iGluR.

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