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El acoplamiento espacio-temporal del transportador cAMP a la función del canal de cloruro CFTR en el epitelio
Chunying Li1, Partha C Krishnamurthy, Himabindu Penmatsa
1Department of Physiology, The University of Tennessee Health Science Center, 894 Union Avenue, 420 Nash, Memphis, TN 38163, USA.
Cell
|November 30, 2007
Resumen
La proteína 4 de resistencia a múltiples fármacos (MRP4), un transportador de cAMP, se asocia física y funcionalmente con el regulador de conductividad transmembrana de la fibrosis quística (CFTR). La inhibición de MRP4 mejora la función CFTR y protege contra la diarrea secretora.
Área de la Ciencia:
- Biología celular Biología celular.
- Fisiología Molecular Fisiología Molecular
- Gastroenterología y Gastroenterología.
Sus antecedentes:
- El regulador de conductividad transmembrana de la fibrosis quística (CFTR) es un canal de cloruro regulado por cAMP crucial para la función epitelial.
- El CFTR forma complejos macromoleculares con varias moléculas de señalización y transportadoras en la membrana celular apical.
Objetivo del estudio:
- Investigar la asociación funcional y física entre el CFTR y el transportador de cAMP, la proteína 4 de resistencia a múltiples fármacos (MRP4).
- Aclarar el papel de esta interacción en la regulación de las corrientes de cloruro mediadas por la CFTR y la dinámica de la cAMP.
- Para determinar las implicaciones de este complejo en los trastornos gastrointestinales.
Principales métodos:
- Ensayos funcionales que miden las corrientes de cloruro mediadas por CFTR.
- Grabaciones de un solo canal de la actividad del CFTR.
- Förster las mediciones basadas en la transferencia de energía de resonancia (FRET) de la dinámica cAMP intracelular.
- Estudios que utilizan la inhibición de MRP4 y el noqueo de Mrp4 en ratones.
Principales resultados:
- MRP4 se asocia física y funcionalmente con CFTR a través de la proteína de andamio PDZ PDZK1.1.
- La inhibición de MRP4 potencia las corrientes CFTR estimuladas por adenosina al reducir el eflujo cAMP apical.
- La interrupción del complejo CFTR-MRP4-PDZK1 anula este acoplamiento funcional.
- Los ratones con knockout de Mrp4 exhiben una mayor susceptibilidad a la diarrea secretora mediada por CFTR.
Conclusiones:
- Existe un nuevo complejo macromolecular que involucra a CFTR, MRP4 y PDZK1 en la superficie apical del epitelio intestinal.
- Este complejo juega un papel crítico en la compartimentación de la cAMP y la regulación de la función CFTR.
- La desregulación de este complejo tiene implicaciones significativas para la diarrea secretora y la enfermedad inflamatoria intestinal.
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