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Se requieren trifosfatos nucleósidos para abrir el canal de cloruro de la CFTR
M P Anderson1, H A Berger, D P Rich
1Howard Hughes Medical Institute, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242.
Cell
|November 15, 1991
Resumen
El ATP citosólico es esencial para la apertura de los canales de CFTR fosforilados, con la hidrólisis por el dominio de unión de nucleótidos 1 (NBD1) potencialmente suficiente para la activación. Esto explica cómo las mutaciones de la CFTR interrumpen la función del canal de cloruro.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Fisiología del canal iónico Fisiología del canal iónico
- La bioquímica es la bioquímica.
Sus antecedentes:
- El canal de cloruro del regulador de conductividad transmembrana de la fibrosis quística (CFTR) posee dos dominios de unión de nucleótidos (NBD1 y NBD2).
- La función del canal CFTR es crucial para el transporte de iones, y las mutaciones en los NBD están vinculadas a la fibrosis quística.
Objetivo del estudio:
- Investigar el papel del trifosfato de adenosina (ATP) y otros trifosfatos nucleósidos en la regulación de la actividad del canal CFTR.
- Para dilucidar el mecanismo por el cual la hidrólisis de ATP influye en el encierro del canal CFTR.
Principales métodos:
- Utilizó la proteína quinasa dependiente de cAMP (PKA) para la fosforilación del CFTR.
- Se evaluó la actividad del canal utilizando varios análogos de nucleótidos hidrolizables y no hidrolizables.
- Se examinaron mutantes del CFTR para determinar el papel de dominios específicos en la regulación dependiente del ATP.
Principales resultados:
- Los canales de CFTR fosforilados requieren ATP citosólico para su apertura, activado a través de una vía independiente de PKA.
- Los nucleótidos hidrolizables (ATP, GTP, ITP, UTP, CTP) activaron los canales fosforilados, mientras que los análogos no hidrolizables y el ATP libre de Mg2+ no lo hicieron.
- El ATP parece controlar la actividad de la CFTR independientemente del dominio R, con la hidrólisis de NBD1 potencialmente suficiente para la apertura.
Conclusiones:
- Los nucleósidos trifosfatados, en particular el ATP, son reguladores críticos de la función del canal CFTR.
- La hidrólisis de ATP, probablemente por NBD1, es un paso clave en la apertura del canal CFTR.
- Estos hallazgos proporcionan información sobre cómo las mutaciones de NBD en CFTR conducen a la función deteriorada de los canales de cloruro y la fibrosis quística.
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