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1 Department of Pharmacology, University of South Alabama College of Medicine, Mobile, Alabama 36688; and 2 University of Colorado Health Sciences Center, Denver, Colorado 80262
Activation of store-operated Ca2+ entry inhibits type 6 adenylyl cyclase (EC 4.6.1.1; AC6; Yoshimura M and Cooper DM. Proc Natl Acad Sci USA 89: 6712-6720, 1992) activity in pulmonary artery endothelial cells. However, in lung microvascular endothelial cells (PMVEC), which express AC6 and turn over cAMP at a rapid rate, inhibition of global (whole cell) cAMP is not resolved after direct activation of store-operated Ca2+ entry using thapsigargin. Present studies sought to determine whether the high constitutive phosphodiesterase activity in PMVECs rapidly hydrolyzes cAMP so that Ca2+ inhibition of AC6 is difficult to resolve. Direct stimulation of adenylyl cyclase using forskolin and inhibition of type 4 phosphodiesterases using rolipram increased cAMP and revealed Ca2+ inhibition of AC6. Enzyme activity was assessed using PMVEC membranes, where Ca2+ and cAMP concentrations were independently controlled. Endogenous AC6 activity exhibited high- and low-affinity Ca2+ inhibition, similar to that observed in C6-2B cells, which predominantly express AC6. Ca2+ inhibition of AC6 in PMVEC membranes was observed after enzyme activation and inhibition of phosphodiesterase activity and was independent of the free cAMP concentration. Thus, under basal conditions, the constitutive type 4 phosphodiesterase activity rapidly hydrolyzes cAMP so that Ca2+ inhibition of AC6 is difficult to resolve, indicating that high phosphodiesterase activity works coordinately with AC6 to regulate membrane-delimited cAMP concentrations, which is important for control of cell-cell apposition.
signal transduction; endothelial cells; permeability; lung
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