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El difosfato de adenosina como un regulador intracelular de la secreción de insulina
C G Nichols1, S L Shyng, A Nestorowicz
1Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. cnichols@cellbio.wustl.edu
Science (New York, N.Y.)
|June 21, 1996
Resumen
Las mutaciones en el receptor de sulfonilurea NBF2 alteran la forma en que los canales de potasio sensibles al trifosfato de adenosina (KATP) responden a los cambios metabólicos, lo que afecta la secreción de insulina. El MgADP intracelular puede regular estos canales al unirse a SUR NBF2.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Endocrinología Endocrinología.
Sus antecedentes:
- Los canales de potasio (KATP) sensibles al trifosfato de adenosina (ATP) vinculan el metabolismo celular con la actividad eléctrica, crucial para la secreción de insulina pancreática.
- Estos canales están regulados por nucleótidos intracelulares como el ATP y el difosfato de adenosina (ADP).
Objetivo del estudio:
- Para investigar el papel del segundo pliegue de unión de nucleótidos (NBF2) del receptor de sulfonilurea (SUR) en la regulación del canal KATP.
- Comprender el impacto de las mutaciones SUR específicas en la función del canal y la secreción de insulina.
Principales métodos:
- Mutagénesis dirigida al sitio del gen SUR, centrada en NBF2.
- Análisis electrofisiológico de la actividad del canal KATP en respuesta a diversas concentraciones de nucleótidos y agentes farmacológicos.
- Comparación de los fenotipos de canal de tipo salvaje y mutante.
Principales resultados:
- Una mutación en SUR NBF2 causó que los canales KATP se abrieran con el diazóxido, pero perdieran sensibilidad a la inhibición metabólica.
- La mutación análoga en el hámster SUR deterioró el antagonismo del difosfato de adenosina (ADP) de la inhibición del ATP.
- Otras mutaciones de NBF2 replicaron este fenotipo, mientras que una mutación similar en NBF1 no afectó la sensibilidad a MgADP.
Conclusiones:
- La unión intracelular de MgADP a SUR NBF2 es crítica para antagonizar la inhibición de ATP de los canales KATP.
- La disfunción de SUR NBF2 puede conducir a una regulación deteriorada de la secreción de insulina, como se ve en la hipoglucemia hiperinsulinémica persistente de la infancia.
- La interacción de MgADP con SUR NBF2 representa un mecanismo regulador clave para la secreción de insulina.
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