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Activación provocada por irritantes y modulación del calcio del receptor TRPA1
Jianhua Zhao1, John V Lin King2,3, Candice E Paulsen2,4
1Department of Biochemistry and Biophysics and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
Nature
|July 10, 2020
Resumen
El canal de iones potencial del receptor transitorio TRPA1 detecta los irritantes. Los estudios estructurales revelan un mecanismo de modificación de cisteína en dos pasos que controla el flujo de iones y la unión de calcio, lo que explica la señalización del dolor y la picazón.
Área de la Ciencia:
- La neurociencia
- Biología molecular
- La bioquímica
Sus antecedentes:
- El canal iónico potencial del receptor transitorio TRPA1 (TRPA1) detecta los irritantes ambientales y media el dolor y la picazón inflamatorios.
- La activación de TRPA1 por electrófilos y segundos mensajeros es crucial para las vías de dolor y picazón, por lo que es un objetivo terapéutico.
- Los mecanismos moleculares precisos de la activación de TRPA1 por los irritantes y su regulación por el calcio siguen sin estar claros.
Objetivo del estudio:
- Aclarar los mecanismos estructurales por los cuales TRPA1 reconoce y responde a los irritantes electrófilos.
- Comprender el papel de los residuos de cisteína y los bucles citoplasmáticos en la apertura del canal TRPA1.
- Para caracterizar el bolsillo de unión de calcio y su papel en la regulación TRPA1.
Principales métodos:
- Cristalografía de rayos X y microscopía cryoelectrónica para la determinación estructural.
- Registros electrofisiológicos para evaluar la actividad del canal y la permeación iónica.
- Mutagénesis dirigida al sitio para investigar la función de residuos y bucles específicos de cisteína.
Principales resultados:
- Los electrófilos activan TRPA1 a través de un proceso de modificación de cisteína en dos pasos (C621 y C665), estabilizando una conformación de bucle de activación.
- Este mecanismo modula el filtro de selectividad y una puerta citoplasmática, mejorando la permeabilidad del calcio y el flujo iónico.
- Se identificó una bolsa de unión de calcio conservada, lo que explica la potenciación dependiente de calcio, la desensibilización y la activación operada por el receptor.
Conclusiones:
- Se propone un modelo estructural detallado para la activación de TRPA1 por electrófilos, que vincula la detección química con el control de canales.
- Los hallazgos proporcionan una base estructural para comprender cómo TRPA1 media las respuestas al dolor y a la picazón.
- El bolsillo de unión de calcio conservado ofrece información sobre la regulación del canal TRP en todos los subtipos.
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