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Los compuestos nocivos activan los canales iónicos TRPA1 a través de la modificación covalente de las cisteínas

Lindsey J Macpherson¹, Adrienne E Dubin, Michael J Evans

¹Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

|January 24, 2007

Resumen

Los canales TRPA1, activados por los irritantes, señalan el dolor mediante la modificación covalente de los residuos de cisteína. Esta unión covalente, particularmente de las cisteínas reactivas, desencadena la activación del canal y la señalización del dolor.

Área de la Ciencia:

La neurociencia es la neurociencia.
Biología Molecular Biología Molecular
La bioquímica es la bioquímica.

Sus antecedentes:

Las neuronas nociceptivas detectan el daño periférico, transmitiendo señales de dolor a través del sistema nervioso.
TRPA1 (canal A1 del potencial del receptor transitorio) se expresa en las neuronas nociceptivas y se activa por diversos estímulos nocivos como el frío y los irritantes.
El mecanismo preciso de la activación de TRPA1 por diversos estímulos sigue siendo en gran medida desconocido.

Objetivo del estudio:

Para investigar el papel de la modificación covalente de los residuos de cisteína en la activación del canal TRPA1.
Para dilucidar cómo diversos estímulos activan los canales TRPA1.

Principales métodos:

Utilizó la química de clic para demostrar la unión covalente del aceite de mostaza y los derivados de cinamaldehído al ratón TRPA1.1.
Se emplearon agentes modificadores de la cisteína como la iodoacetamida (IA) y el (2-aminoetil) metanetiosulfonato (MTSEA) para investigar la activación de TRPA1.
Se identificaron residuos específicos de cisteína TRPA1 involucrados en la función del canal utilizando espectrometría de masas.
Realizó registros electrofisiológicos en parches extirpados para evaluar las corrientes TRPA1 y el efecto de los compuestos reactivos, el lavado y los agentes reductores (DTT).

Principales resultados:

El aceite de mostaza y los derivados de cinnamaldehyde se unen covalentemente al ratón TRPA1.1.
Los agentes IA y MTSEA no relacionados estructuralmente también unen y activan TRPA1.
La espectrometría de masas identificó catorce cisteínas citosólicas TRPA1 modificadas por IA, con tres cruciales para la función normal.
Los compuestos reactivos indujeron que las corrientes TRPA1 se mantuvieran después del lavado; la activación inducida por MTSEA fue bloqueada por DTT.

Conclusiones:

La modificación covalente de las cisteínas reactivas en TRPA1 es un mecanismo clave para la activación del canal.
Esta modificación covalente rápidamente señala el daño tisular potencial a través de la vía del dolor.
Comprender la reactividad de la cisteína de TRPA1 proporciona información sobre la señalización del dolor y los posibles objetivos terapéuticos.

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