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Control óptico de los receptores de dopamina mediante el uso de un agonista inverso atado con interruptor fotográfico
Prashant C Donthamsetti1, Nils Winter2, Matthias Schönberger2
1Department of Molecular and Cell Biology, University of California , Berkeley, California 94720, United States.
Journal of the American Chemical Society
|November 23, 2017
Resumen
Los científicos diseñaron receptores de dopamina (DAR) para el control remoto de la luz utilizando ligandos atados con conmutación fotográfica. Este avance permite una modulación espacial y temporal precisa de las GPCR, ofreciendo nuevas estrategias terapéuticas.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- La neurociencia
Sus antecedentes:
- Los receptores acoplados a proteínas G de la familia A (GPCR) son cruciales para los procesos biológicos y las aplicaciones clínicas.
- La rodopsina, un GPCR de la familia A, es sensible a la luz debido a su enlace covalente con la retina.
- La mayoría de los GPCR carecen de sensibilidad a la luz y unión al ligando covalente, lo que limita las posibilidades de control remoto.
Objetivo del estudio:
- Para diseñar GPCRs de la familia A insensibles a la luz para un control remoto y preciso, imitando la sensibilidad a la luz de la rodopsina.
- Desarrollar un método para la modulación espacial-temporal de la actividad de la GPCR específica del receptor y del tipo de célula.
- Investigar el potencial de los ligandos atados fotointercambiables (PTL) para el control de los receptores de dopamina (DAR).
Principales métodos:
- Conjugación de un derivado de azobenzeno de un ligando del receptor de dopamina (PPHT) con residuos de cisteína diseñados cerca del sitio de unión de la dopamina.
- Utilizando las PTL para lograr un bloqueo rápido, reversible y selectivo de los receptores de dopamina D1 y D2 (D1R y D2R).
- Investigando el comportamiento del ligando como un antagonista neutro atado fotoswitchable o agonista inverso basado en el sitio de atado.
Principales resultados:
- Ingeniería química exitosa de DAR para el control remoto selectivo a través de la luz.
- Se ha demostrado un bloqueo rápido, reversible y selectivo de D1R y D2R utilizando PTL.
- Se observó una actividad variada del ligando (antagonista o agonista inverso) basada en el sitio de conjugación PTL.
Conclusiones:
- Los receptores de dopamina pueden ser diseñados para un control remoto preciso utilizando ligandos activados por luz.
- Este enfoque proporciona una plantilla versátil para el control de precisión de varios GPCR de la familia A.
- Los hallazgos abren caminos para nuevas estrategias terapéuticas dirigidas a los GPCR con precisión espacio-temporal.
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