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Title

Mechanisms underlying the activation of L-type calcium channels by urocortin in rat ventricular myocytes

AuthorsSmani, Tarik; Calderón-Sánchez, Eva; Gómez-Hurtado, Nieves; Fernández-Velasco, María ; Cachofeiro, Victoria; Ordóñez Fernández, Antonio ; Delgado, Carmen
KeywordsUrocortin
L-type calcium channels
Patch-clamp
PKC
ERK1/2
Issue Date2010
PublisherOxford University Press
European Society of Cardiology
CitationCardiovascular Research 87(3): 459-466 (2010)
Abstract[Aims]: The aim of this study was to elucidate the signalling pathways implicated in the modulation of cardiac L-type Ca2+ channels by urocortin (Ucn) in ventricular myocytes. [Methods and results]: Adult rat ventricular myocytes were stimulated in vitro with Ucn for 20–40 min. L-type calcium currents (ICaL) were measured with the patch-clamp technique, whereas quantification of activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was assessed by sandwich-ELISA. Ucn induced a significant increase in ICaL density that was not prevented by the protein kinase A (PKA) inhibitor KT-5720 or the non-selective antagonist of guanine nucleotide exchange factor brefeldin A. The Ucn effect was antagonized by astressin, a corticotropin-releasing factor receptor-2 (CRF-R2) antagonist, and significantly reduced by protein kinase C (PKC) and ERK1/2 inhibitors. The cyclic AMP (cAMP) analogue 8-pCPT-2′OMe-cAMP, which selectively activates the exchange protein activated by cAMP (Epac), was ineffective in modifying ICaL. Analysis of phospho-ERK1/2 showed that Ucn induced a significant activation of the ERK1/2 pathway in ventricular myocytes and this effect was prevented by pre-incubation with PKC inhibitors. [Conclusion]: The present study provides evidence of new mechanisms involved in the modulation of L-type Ca2+ channels by Ucn in adult ventricular myocytes. We propose that the marked increase in ICaL density induced by Ucn is mediated through CRF-R2 and involves PKC-dependent activation of the ERK1/2 pathway, whereas PKA and Epac signalling are not implicated.
Description8 páginas, 7 figuras.
Publisher version (URL)http://dx.doi.org/10.1093/cvr/cvq063
URIhttp://hdl.handle.net/10261/42360
DOI10.1093/cvr/cvq063
ISSN0008-6363
E-ISSN1755-3245
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