INHIBITION OF AGONIST-MEDIATED CALCIUM-ENTRY BY CALMODULIN ANTAGONISTS AND BY THE CA2+ CALMODULIN KINASE-II INHIBITOR KN-62 - STUDIES WITH THYROID FRTL-5 CELLS/

Calmodulin and calmodulin-dependent mechanisms are probably important in regulating thyroid cell function. However, calmodulin antagonists m ay directly modify calcium fluxes in cells. In the present investigati on the effects of several calmodulin inhibitors and of KN-62, a specif ic calcium/calmodulin kinase II inhibitor, on the ATP- and thapsigargi n-evoked changes in intracellular free calcium ([Ca2+](i)) were invest igated in Fura-2 loaded thyroid FRTL-5 cells. All of the inhibitors te sted attenuated agonist-evoked calcium entry. The inhibitor calmidazol ium per se potently released sequestered calcium followed by enhanced calcium entry. Pretreatment of the cells with calmidazolium inhibited both the thapsigargin- and the ATP-evoked calcium entry. Our results s how that calmodulin antagonists are potent inhibitors of calcium entry in thyroid cells, possibly by directly inhibiting the calcium entry p athway. This inhibition may explain, in part, the results obtained wit h calmodulin inhibitors in previous studies.