TRIETHYLTIN INTERFERES WITH CA2+ SIGNALING AND POTENTIATES NOREPINEPHRINE RELEASE IN PC12 CELLS

We have investigated the effects of triethyltin (TET) on agonist-stimu lated Ca2+ signaling and neurosecretion in PC12 cells, Treatment of PC 12 cells with 10 mu M TET elicited a slow increase of the resting cyto solic free Ca2+ concentration due to Ca2+ release from intracellular s tores, Furthermore, TET modified the Ca2+ responses elicited by bradyk inin (Bk), adenosine triphosphate (ATP), or high K+. TET potentiated t he peak Ca2+ response stimulated by Bk in both the presence and the ab sence of extracellular Ca2+, and prolonged the recovery phase after AT P stimulation. Ln contrast, the Ca2+ transient elicited by bathing cel ls in high K+ was markedly reduced, suggesting that TET can differenti ally affect several targets on Ca2+-signaling pathways. Neurotransmitt er depletion follows in vivo exposure to TET, Since neurotransmitter s ecretion is strictly dependent on intracellular Ca2+ signals we also i nvestigated whether treatment with TET modified norepinephrine release from PC12 cells, TET did not elicit norepinephrine release, but it en hanced the release of norepinephrine induced by Bk or ATP, The increas ed release of norepinephrine elicited in combination with Bk was indep endent from extracellular Ca2+. Our results suggest that possible neur otoxic effects of TET can derive from its ability to modulate Ca2+ sig naling and eventually neurosecretion. (C) 1996 Academic Press, Inc.