Journal
JOURNAL OF CELL BIOLOGY
Volume 157, Issue 7, Pages 1267-1278Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200204022
Keywords
adenosine 3 ',5 '-cyclic monophosphate; cAMP; store-operated calcium entry; thrombin; permeability
Categories
Funding
- NHLBI NIH HHS [P01 HL066299, R01 HL60024, P01 HL66299, R01 HL060024] Funding Source: Medline
- NIGMS NIH HHS [R01 GM32483, R01 GM032483] Funding Source: Medline
Ask authors/readers for more resources
A cute 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 (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 [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 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 [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 AC(6) is essential for endothelial gap formation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available