GENISTEIN INHIBITS CALCIUM-RELEASE BY PLATELET-DERIVED GROWTH-FACTOR BUT NOT BRADYKININ OR CADMIUM IN HUMAN FIBROBLASTS

Cd2+ provokes inositol trisphosphate production and releases stored Ca 2+, apparently by binding to a zinc site in the external domain of an orphan receptor. One muM Cd2+ evokes an immediate spike in cytosolic f ree Ca2+, which is similar to that evoked by bradykinin. Platelet-deri ved growth factor (PDGF) also increases free Ca2+ inhuman dermal fibro blasts, but there is a distinct lag before free Ca2+ rises in response to PDGF. Genistein, which selectively inhibits tyrosine kinases, mark edly inhibited Ca2+ mobilization evoked by PDGF. Calcium mobilization triggered by cadmium or bradykinin was relatively insensitive to genis tein. The PDGF receptor is known to be a tyrosine kinase, which phosph orylates and thereby activates phospholipase Cgamma, whereas a G prote in couples the bradykinin receptor to another phospholipase C isoform. These findings support the hypothesis that the orphan receptor trigge red by cadmium is coupled to phospholipase C via a G protein.