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1 Physiology, Loyola University Chicago, Maywood, IL, USA
* To whom correspondence should be addressed. E-mail: lblatte{at}lumc.edu.
The effects of inhibitors of Ca2+/calmodulin-dependent protein kinase II (CaMKII) on intracellular Ca2+ signaling were examined in single calf pulmonary artery endothelial (CPAE) cells, using indo-1 microfluorimetry to measure cytoplasmic Ca2+ concentration ([Ca2+]i). The three CaMKII inhibitors, KN-93, KN-62 and the autocamtide-2 related inhibitory peptide (AIP), all reduced the plateau phase of the [Ca2+] transient evoked by stimulation with extracellular ATP. Exposure to KN-93 or AIP alone in the presence of 2 mM extracellular Ca2+ resulted in a dose-dependent increase of [Ca2+]i consisting of rapid and transient Ca2+ spike followed by a small sustained plateau phase of elevated [Ca2+]i. Exposure to KN-93 in the absence of extracellular Ca2+ caused a transient rise of [Ca2+]i, suggesting that exposure to CaMKII inhibitors directly triggered release of Ca2+ from intracellular endoplasmic reticulum (ER) Ca2+-stores. Repetitive stimulation with KN-93 and ATP, respectively, revealed that both components released Ca2+ largely from the same store. Pretreatment of CPAE cells with the membrane permeable IP3 receptor blocker 2-APB caused a significant inhibition of the KN-93-induced Ca2+ response, suggesting that exposure to KN-93 affects Ca2+ release from an IP3-sensitive store. Depletion of Ca2+ stores by exposure to ATP or to the ER Ca2+ pump inhibitor thapsigargin triggered robust capacitative Ca2+ entry (CCE) signals in CPAE cells which could be blocked effectively with KN-93. The data suggest that in CPAE cells CaMKII modulates Ca2+ handling at different levels. The use of CaMKII inhibitors revealed that in CPAE cells the most profound effects of CaMKII are inhibition of release of Ca2+ from intracellular stores and activation of CCE.
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