Mechanism of damnacanthal-induced [Ca2+]i elevation in human dermal fibroblasts

Damnacanthal is a potent and selective inhibitor of p56(lck) tyrosine kinase in a variety of tissues. We have found, however, using the Ca2+ microfluorimetry technique, that damnacanthal releases intracellular Ca2+ stores and promotes Ca2+ entry in human dermal fibroblasts. The effect of damnacanthal on the peak [Ca2+](i) values and the latent time to the peak was concentration-dependent. Damnacanthal releases Ca2+ from thapsigargin-sensitive Ca2+ stores, and the Ca2+ stores responding to damnacanthal were overlapped with those of bradykinin. Damnacanthal-induced Ca2+ entry was mediated by voltage-dependent and voltage-independent Ca2+ channels. This effect of damnacanthal on intracellular Ca2+ mobilization was also observed in cultured bovine coronary endothelial cells but not demonstrated in freshly isolated rat basilar smooth muscle cells. Our study suggests that damnacanthal increases intracellular Ca2+ by releasing Ca2+ from internal stores and promoting Ca2+ entry. The relationship between the actions of damnacanthal on tyrosine kinase and intracellular Ca2+ requires further investigation. (C) 2000 Elsevier Science B.V. All rights reserved.