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El receptor beta2-adrenérgico interactúa con el factor regulador del intercambiador Na+/H+ para controlar el
R A Hall1, R T Premont, C W Chow
1Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature
|April 29, 1998
Resumen
Los receptores beta2-adrenérgicos regulan el pH celular a través del intercambio Na+/H+. La unión agonista une directamente estos receptores al NHERF, un regulador clave del intercambiador Na+/H+ 3, independiente de la señalización de la proteína G.
Área de la Ciencia:
- Biología celular Biología celular.
- Farmacología molecular farmacología molecular.
- Fisiología Fisiología Fisiología.
Sus antecedentes:
- Los receptores beta2-adrenérgicos (β2ARs) median las respuestas celulares a través de las proteínas G.
- Algunos efectos β2AR, como la regulación del pH, no se explican completamente por las vías de la proteína G.
- La actividad del intercambiador Na+/H+ (NHE) es crucial para la homeostasis del pH celular.
Objetivo del estudio:
- Investigar el mecanismo de la regulación mediada por β2AR de la función del intercambiador Na+/H+ (NHE).
- Para determinar si los β2AR interactúan directamente con las proteínas involucradas en la regulación de la NHE.
- Para aclarar el papel de las vías independientes de la proteína G en la señalización β2AR.
Principales métodos:
- Se estudió la asociación promovida por el agonista entre β2AR y el factor regulador del intercambiador Na+/H+ (NHERF).
- Se utilizó el análisis de la interacción mediada por el dominio PDZ.
- Mutagénesis dirigida al sitio empleada del dominio C-terminal β2AR (mutación de L a A).
- Regulación evaluada de la actividad del intercambiador Na+/H+ tipo 3 (NHE3) y la activación de la adenilil ciclasa.
Principales resultados:
- Se ha demostrado la unión directa agonista-dependiente de β2AR a NHERF.
- Se identificó una interacción PDZ-dominio entre NHERF y el extremo C de β2AR.
- Se demostró que la mutación del residuo de leucina terminal C de β2AR abolió la interacción NHERF.
- Se observó que esta mutación alteró la regulación β2AR de NHE3 pero no la actividad de la adenilil ciclasa.
Conclusiones:
- La unión agonista-dependiente de NHERF a β2AR es un nuevo mecanismo para la señalización de β2AR.
- Esta interacción juega un papel importante en la regulación mediada por β2AR del intercambio Na+/H+.
- Sugiere una vía independiente de la proteína G para el control β2AR del pH celular.
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