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Organización y funciones de los complejos de receptores mGlu y GABA_B

Jean-Philippe Pin^1,2, Bernhard Bettler³

¹Centre National de la Recherche Scientifique UMR 5203, Institut de Génomique Fonctionnelle, Université de Montpellier, F-34094 Montpellier, France.

|December 2, 2016

Resumen

El glutamato metabotrópico (mGlu) y los receptores < sub> B < sub> GABA son receptores atípicos acoplados a la proteína G (GPCR) cruciales para la función cerebral. Comprender su compleja estructura y mecanismos de activación ofrece nuevos objetivos terapéuticos para trastornos neurológicos y de salud mental.

Área de la Ciencia:

La neurociencia
Biología molecular
Farmacología

Sus antecedentes:

El glutamato y el ácido gamma-aminobutírico (GABA) son neurotransmisores clave que median la señalización sináptica.
Estos neurotransmisores activan tanto los canales iónicos ligandos rápidos como los receptores acoplados a proteínas G (GPCR) más lentos.
El glutamato metabotrópico (mGlu) y los receptores GABA_B son GPCR atípicos caracterizados por grandes dominios extracelulares y estructuras diméricas obligadas.

Objetivo del estudio:

Para aclarar las características estructurales y funcionales de los receptores mGlu y GABA_B.
Investigar los mecanismos alostéricos que rigen la activación de estos GPCR atípicos.
Explorar el potencial terapéutico de dirigirse a estos receptores para condiciones de salud neurológica y mental.

Principales métodos:

Técnicas de biología estructural (por ejemplo, crio-EM, cristalografía de rayos X) para determinar la arquitectura del receptor.
Ensayos bioquímicos y biofísicos para estudiar la activación de los receptores y la modulación alostérica.
Ensayos basados en células para investigar las interacciones receptor-proteína y las vías de señalización.

Principales resultados:

Reveló las intrincadas estructuras de los receptores mGlu y GABA_B, destacando sus grandes dominios extracelulares e interfaces diméricas.
Se demostró el papel crítico de las múltiples interacciones alostéricas entre los dominios de las subunidades en la activación de los receptores.
Se identificaron asociaciones extensas con varias proteínas de tráfico, efectoras y reguladoras, aumentando aún más la complejidad molecular.

Conclusiones:

Las características estructurales únicas y los mecanismos de activación complejos de los receptores mGlu y GABA_B son clave para su función.
Estos receptores representan objetivos prometedores para las intervenciones terapéuticas en una serie de trastornos neurológicos y de salud mental.
Una mayor investigación sobre sus relaciones estructura-composición-función facilitará el desarrollo de nuevas terapias.

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