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Los neurosteroides endógenos regulan los receptores GABAA a través de dos sitios discretos de transmembrana
Alastair M Hosie1, Megan E Wilkins, Helena M A da Silva
1Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. t.smart@ucl.ac.uk
Nature
|November 17, 2006
Resumen
Los neurosteroides modulan la neurotransmisión inhibidora a través de los receptores GABA (A) en dos sitios distintos. Comprender estos sitios de unión es clave para desarrollar tratamientos para afecciones como la depresión y la ansiedad.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- Biología Molecular Biología Molecular
- Farmacología Farmacología.
Sus antecedentes:
- La neurotransmisión inhibidora mediada por los receptores GABA (A) es modulada por neurosteroides endógenos.
- Los neurosteroides se sintetizan en el cerebro durante el estrés, el embarazo y el consumo de etanol.
- La regulación neurosteroide interrumpida de la transmisión GABAérgica está relacionada con el trastorno de pánico, la depresión, la esquizofrenia, la dependencia del alcohol y la epilepsia.
Objetivo del estudio:
- Para identificar los sitios específicos de unión a través de los cuales los neurosteroides interactúan con los receptores GABA (A).
- Para dilucidar los mecanismos de potenciación de los neurosteroides y la activación directa de los receptores GABA.
- Comprender las funciones fisiológicas y fisiopatológicas de los neurosteroides en el cerebro.
Principales métodos:
- Identificación de dos sitios de unión neurosteroides discretos dentro de los dominios transmembranales del receptor GABA.
- Caracterización de las funciones de estos sitios en la potenciación de las respuestas GABA y la activación directa del receptor.
- Análisis de la conservación de estos sitios en toda la familia de receptores GABA (A).
Principales resultados:
- Se identificaron dos sitios de unión discretos: uno en los dominios transmembranares de la subunidad alfa para la potenciación, y otro en la interfaz de la subunidad alfa-beta para la activación directa.
- La potenciación neurosteroide de las respuestas GABA ocurre en el sitio de la subunidad alfa.
- La activación directa del receptor se inicia en la interfaz alfa-beta y se mejora al unirse al sitio de potenciación, lo que requiere la ocupación de ambos sitios para una activación significativa.
Conclusiones:
- La acción de los neurosteroides sobre los receptores GABA (A) implica dos sitios de unión distintos y conservados.
- La identificación de estos sitios ofrece una vía para desarrollar nuevas terapias basadas en neurosteroides.
- Esta investigación proporciona una base para la creación de modelos de enfermedades para la disfunción neurosteroide.
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