Mechanism of damnacanthal-induced [Ca(2+)](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 Ca(2+) microfluorimetry technique, that damnacanthal releases intracellular Ca(2+) stores and promotes Ca(2+) entry in human dermal fibroblasts. The effect of damnacanthal on the peak [Ca(2+)](i) values and the latent time to the peak was concentration-dependent. Damnacanthal releases Ca(2+) from thapsigargin-sensitive Ca(2+) stores, and the Ca(2+) stores responding to damnacanthal were overlapped with those of bradykinin. Damnacanthal-induced Ca(2+) entry was mediated by voltage-dependent and voltage-independent Ca(2+) channels. This effect of damnacanthal on intracellular Ca(2+) 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 Ca(2+) by releasing Ca(2+) from internal stores and promoting Ca(2+) entry. The relationship between the actions of damnacanthal on tyrosine kinase and intracellular Ca(2+) requires further investigation.