Journal
BIOMEDICINE-TAIWAN
Volume 3, Issue 3, Pages 130-139Publisher
EDP SCIENCES S A
DOI: 10.1016/j.biomed.2012.11.003
Keywords
Ca2+ store depletion; beta-cell; RINm5F cells; voltage-gated Ca2+ channel
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Funding
- China Medical University, Taiwan
- Taiwan National Science Council [CMU99-S-16, NSC97-2320-B-039-029-MY3]
- China Medical University Hospital [DMR-96-112]
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Background: Glucose-stimulated insulin secretion in pancreatic islet beta-cells is initiated by ATP-induced closure of ATP-sensitive potassium channels (K-ATP channels), subsequent depolarization and opening of voltage-gated Ca2+ channels (VGCC), eventually leading to insulin exocytosis. A variety of natural and environmental toxins have been known to cause Ca2+ store depletion and consequently death in many cell types, but the impact of sustained Ca2+ store depletion on beta-cell plasmalemmal ion channels is unknown. Purpose: This report examined whether sustained Ca2+ store depletion induced by cyclopiazonic acid (CPA) could affect voltage-gated ion channels and K-ATP channels in rat insulinoma RINm5F cells. Methods: Microfluorimetric Ca2+ imaging and patch-clamping experiments were employed in this study. Results: Glucose-and KCl-stimulated Ca2+ signals were substantially attenuated after a 24-h CPA treatment. Consistently, patch clamp experiments also demonstrated that VGCC currents were much reduced after a 24-h CPA treatment. Quantitative RT-PCR experiments showed that gene expression of alpha-1A and alpha-1C was reduced, suggesting that expression of P/Q-and L-type VGCC was down-regulated. Voltage-gated K+ channels, K-ATP channels and store-operated Ca2+ entry were, however, unaffected. Inhibition of extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) could not rescue the KCl-stimulted Ca2+ signal attenuated by sustained Ca2+ store depletion. Conclusion: Our work shows, for the first time, that sustained Ca2+ store depletion in insulinoma RINm5F cells leads to selective down-regulation of VGCC possibly via pathways other than ERK or JNK. Copyright (C) 2012, China Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
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