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Published 24 June 2002. doi:10.1083/jcb.200204022
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© The Rockefeller University Press, 0021-9525/2002/6/1267 $5.00
The Journal of Cell Biology, Volume 157, Number 7, June 24, 2002 1267-1278

Article

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

Donna L. Cioffi1, Timothy M. Moore1, Jerry Schaack3, Judy R. Creighton1, Dermot M.F. Cooper2 and Troy Stevens1

1 Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL 36688
2 Departments of Pharmacology, University of Colorado Health Sciences Center, Denver, CO 80262
3 Microbiology, University of Colorado Health Sciences Center, Denver, CO 80262

Address correspondence to Troy Stevens, Department of Pharmacology, MSB 3364, University of South Alabama College of Medicine, Mobile, AL 36688. Tel.: (251) 460-6010. Fax: (251) 460-6798. E-mail: tstevens{at}jaguar1.usouthal.edu

Acute transitions in cytosolic calcium ([Ca2+]i) through store-operated calcium entry channels catalyze interendothelial cell gap formation that increases permeability. However, the rise in [Ca2+]i only disrupts barrier function in the absence of a rise in cAMP. Discovery that type 6 adenylyl cyclase (AC6; EC 4.6.6.1) is inhibited by calcium entry through store-operated calcium entry pathways provided a plausible explanation for how inflammatory [Ca2+]i mediators may decrease cAMP necessary for endothelial cell gap formation. [Ca2+]i mediators only modestly decrease global cAMP concentrations and thus, to date, the physiological role of AC6 is unresolved. Present studies used an adenoviral construct that expresses the calcium-stimulated AC8 to convert normal calcium inhibition into stimulation of cAMP, within physiologically relevant concentration ranges. Thrombin stimulated a dose-dependent [Ca2+]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 AC8 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 AC6 is essential for endothelial gap formation.

Key Words: adenosine 3',5'-cyclic monophosphate; cAMP; store-operated calcium entry; thrombin; permeability


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