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Glucagon like peptide-1 (GLP-1) is released from intestinal L-cells in response to nutrient ingestion and acts upon pancreatic β-cells potentiating glucose-stimulated insulin secretion and stimulating β-cell proliferation, differentiation, survival and gene transcription. These effects are mediated through the activation of multiple signal transduction pathways including the extracellular regulated kinase (ERK) pathway. We have previously reported that GLP-1 activates ERK through a mechanism dependent upon the influx of extracellular Ca2+ through L-type voltage gated Ca2+ channels (VGCC). However, the mechanism by which L-type VGCCs couple to the ERK signalling pathway in pancreatic β-cells is poorly understood. In this report, we characterise the relationship between L-type VGCC mediated changes in intracellular Ca2+ concentration ([Ca2+]i) and the activation of ERK, and demonstrate that the sustained activation of ERK (up to 30 min) in response to GLP-1 requires the continual activation of the L-type VGCC yet does not require a sustained increase in global [Ca2+]i or Ca2+ efflux from the endoplasmic reticulum. Moreover, sustained elevation of [Ca2+]i induced by ionomycin is insufficient to stimulate the prolonged activation of ERK. Using the cell permeant Ca2+ chelators, EGTA-AM and BAPTA-AM, to determine the spatial dynamics of L-type VGCC-dependent Ca2+ signalling to ERK, we provide evidence that a sustained increase in Ca2+ within the microdomain of the L-type VGCC is sufficient for signalling to ERK and that this plays an important role in GLP-1- stimulated ERK activation.

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Autor(es)

Selway, J. -  Rigatti, R. -  Storey, N. -  Lu, J. -  Willars, G. B. -  Herbert, T. P. - 

Id.: 70138750

Idioma: inglés  - 

Versión: 1.0

Estado: Final

Tipo:  application/pdf - 

Palabras claveB200 Pharmacology, Toxicology and Pharmacy - 

Tipo de recurso: Article  -  PeerReviewed  - 

Tipo de Interactividad: Expositivo

Nivel de Interactividad: muy bajo

Audiencia: Estudiante  -  Profesor  -  Autor  - 

Estructura: Atomic

Coste: no

Copyright: sí

: cc_by4

Formatos:  application/pdf - 

Requerimientos técnicos:  Browser: Any - 

Relación: [References] http://eprints.lincoln.ac.uk/28223/
[References] https://doi.org/10.1371/journal.pone.0033004
[References] 10.1371/journal.pone.0033004

Fecha de contribución: 18-oct-2017

Contacto:

Localización:
* Selway, J. and Rigatti, R. and Storey, N. and Lu, J. and Willars, G. B. and Herbert, T. P. (2012) Evidence that Ca 2+ within the microdomain of the l-type voltage gated Ca 2+ channel activates ERK in MIN6 cells in response to glucagon-like peptide-1. PLoS ONE, 7 (3). 0033004. ISSN 1932-6203

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