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Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase

Acute transitions in cytosolic calcium ([Ca(2+)]i) through store-operated calcium entry channels catalyze interendothelial cell gap formation that increases permeability. However, the rise in [Ca(2+)]i only disrupts barrier function in the absence of a rise in cAMP. Discovery that type 6 adenylyl cy...

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Autores principales: Cioffi, Donna L., Moore, Timothy M., Schaack, Jerry, Creighton, Judy R., Cooper, Dermot M.F., Stevens, Troy
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173565/
https://www.ncbi.nlm.nih.gov/pubmed/12082084
http://dx.doi.org/10.1083/jcb.200204022
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author Cioffi, Donna L.
Moore, Timothy M.
Schaack, Jerry
Creighton, Judy R.
Cooper, Dermot M.F.
Stevens, Troy
author_facet Cioffi, Donna L.
Moore, Timothy M.
Schaack, Jerry
Creighton, Judy R.
Cooper, Dermot M.F.
Stevens, Troy
author_sort Cioffi, Donna L.
collection PubMed
description Acute transitions in cytosolic calcium ([Ca(2+)]i) through store-operated calcium entry channels catalyze interendothelial cell gap formation that increases permeability. However, the rise in [Ca(2+)]i only disrupts barrier function in the absence of a rise in cAMP. Discovery that type 6 adenylyl cyclase (AC(6); EC 4.6.6.1) is inhibited by calcium entry through store-operated calcium entry pathways provided a plausible explanation for how inflammatory [Ca(2+)]i mediators may decrease cAMP necessary for endothelial cell gap formation. [Ca(2+)]i mediators only modestly decrease global cAMP concentrations and thus, to date, the physiological role of AC(6) is unresolved. Present studies used an adenoviral construct that expresses the calcium-stimulated AC(8) to convert normal calcium inhibition into stimulation of cAMP, within physiologically relevant concentration ranges. Thrombin stimulated a dose-dependent [Ca(2+)]i rise in both pulmonary artery (PAECs) and microvascular (PMVEC) endothelial cells, and promoted intercellular gap formation in both cell types. In PAECs, gap formation was progressive over 2 h, whereas in PMVECs, gap formation was rapid (within 10 min) and gaps resealed within 2 h. Expression of AC(8) resulted in a modest calcium stimulation of cAMP, which virtually abolished thrombin-induced gap formation in PMVECs. Findings provide the first direct evidence that calcium inhibition of AC(6) is essential for endothelial gap formation.
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spelling pubmed-21735652008-05-01 Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase Cioffi, Donna L. Moore, Timothy M. Schaack, Jerry Creighton, Judy R. Cooper, Dermot M.F. Stevens, Troy J Cell Biol Article Acute transitions in cytosolic calcium ([Ca(2+)]i) through store-operated calcium entry channels catalyze interendothelial cell gap formation that increases permeability. However, the rise in [Ca(2+)]i only disrupts barrier function in the absence of a rise in cAMP. Discovery that type 6 adenylyl cyclase (AC(6); EC 4.6.6.1) is inhibited by calcium entry through store-operated calcium entry pathways provided a plausible explanation for how inflammatory [Ca(2+)]i mediators may decrease cAMP necessary for endothelial cell gap formation. [Ca(2+)]i mediators only modestly decrease global cAMP concentrations and thus, to date, the physiological role of AC(6) is unresolved. Present studies used an adenoviral construct that expresses the calcium-stimulated AC(8) to convert normal calcium inhibition into stimulation of cAMP, within physiologically relevant concentration ranges. Thrombin stimulated a dose-dependent [Ca(2+)]i rise in both pulmonary artery (PAECs) and microvascular (PMVEC) endothelial cells, and promoted intercellular gap formation in both cell types. In PAECs, gap formation was progressive over 2 h, whereas in PMVECs, gap formation was rapid (within 10 min) and gaps resealed within 2 h. Expression of AC(8) resulted in a modest calcium stimulation of cAMP, which virtually abolished thrombin-induced gap formation in PMVECs. Findings provide the first direct evidence that calcium inhibition of AC(6) is essential for endothelial gap formation. The Rockefeller University Press 2002-06-24 /pmc/articles/PMC2173565/ /pubmed/12082084 http://dx.doi.org/10.1083/jcb.200204022 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Cioffi, Donna L.
Moore, Timothy M.
Schaack, Jerry
Creighton, Judy R.
Cooper, Dermot M.F.
Stevens, Troy
Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase
title Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase
title_full Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase
title_fullStr Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase
title_full_unstemmed Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase
title_short Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase
title_sort dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173565/
https://www.ncbi.nlm.nih.gov/pubmed/12082084
http://dx.doi.org/10.1083/jcb.200204022
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