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La vía CRTC1-SIK1 regula el arrastre del reloj circadiano
Aarti Jagannath1, Rachel Butler1, Sofia I H Godinho1
1Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), University of Oxford, Levels 5-6 West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK; pRED Pharma Research and Development F. Hoffmann-La Roche, 4070 Basel, Switzerland.
Cell
|September 3, 2013
Resumen
La kinasa inducible a la sal 1 (SIK1) regula el restablecimiento del reloj circadiano inhibiendo la vía de la proteína de unión del elemento de respuesta cAMP (CREB). La reducción de SIK1 acelera el reentrenamiento después del jet lag, ofreciendo un objetivo para la regulación del ritmo circadiano.
Área de la Ciencia:
- Cronobiología cronobiología.
- La neurociencia molecular es la neurociencia molecular.
- Biología Molecular Biología Molecular
Sus antecedentes:
- Los ritmos circadianos están sincronizados con el día solar por los fotorreceptores de la retina.
- El restablecimiento fótico del reloj circadiano implica la inducción del gen Per mediada por CREB en el SCN.
- Los mecanismos precisos y los retrasos en el arrastre del reloj circadiano siguen siendo poco conocidos.
Objetivo del estudio:
- Para dilucidar los mecanismos moleculares subyacentes al restablecimiento del reloj circadiano.
- Identificar los reguladores clave de la vía de arrastre fótico en el SCN.
- Investigar el papel de SIK1 y CRTC1 en la dinámica del reloj circadiano.
Principales métodos:
- Análisis del transcriptoma regulado por la luz en los núcleos supraquiasmáticos (SCN).
- Investigando la interacción entre CRTC1, CREB y SIK1.
- Utilizando la eliminación de Sik1 en el SCN para evaluar los cambios de fase del comportamiento y el reentrenamiento.
Principales resultados:
- SIK1 y CRTC1 fueron identificados como componentes cruciales en el restablecimiento del reloj de SCN.
- Los estímulos luminosos promueven la coactivación CRTC1 de CREB, induciendo la expresión de Per1 y Sik1.
- SIK1 retroalimenta negativamente al sistema mediante la fosforilación y desactivación de CRTC1, suprimiendo así los efectos de la luz.
- La eliminación de Sik1 mejoró los cambios de fase del comportamiento y aceleró el reentrenamiento después del jet lag simulado.
Conclusiones:
- SIK1 actúa como un regulador de retroalimentación negativa, limitando el impacto de la luz en el restablecimiento del reloj circadiano.
- La vía SIK1-CRTC1-CREB es un determinante crítico de la velocidad del arrastre circadiano.
- Esta vía representa un objetivo terapéutico potencial para la modulación de los trastornos del ritmo circadiano.
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