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

Damnacanthal is a potent and selective inhibitor of p56(lck) tyrosine kinas e in a variety of tissues. We have found, however, using the Ca2+ microfluo rimetry technique, that damnacanthal releases intracellular Ca2+ stores and promotes Ca2+ entry in human dermal fibroblasts. The effect of damnacantha l on the peak [Ca2+](i) values and the latent time to the peak was concentr ation-dependent. Damnacanthal releases Ca2+ from thapsigargin-sensitive Ca2 + stores, and the Ca2+ stores responding to damnacanthal were overlapped wi th those of bradykinin. Damnacanthal-induced Ca2+ entry was mediated by vol tage-dependent and voltage-independent Ca2+ channels. This effect of damnac anthal on intracellular Ca2+ mobilization was also observed in cultured bov ine coronary endothelial cells but not demonstrated in freshly isolated rat basilar smooth muscle cells. Our study suggests that damnacanthal increase s intracellular Ca2+ by releasing Ca2+ from internal stores and promoting C a2+ entry. The relationship between the actions of damnacanthal on tyrosine kinase and intracellular Ca2+ requires further investigation. (C) 2000 Els evier Science B.V. All rights reserved.