Ca2+-dependent potentiation of muscarinic receptor-mediated Ca2+ elevation

Muscarinic receptor-mediated increases in Ca2+ in SH-SY5Y neuroblastoma cells consist of an initial fast and transient phase followed by a sustained phase. Activation of voltage-gated Ca2+ channels prior to muscarinic stimulation resulted in a several-fold potentiation of the fast phase. Unlike the muscarinic response under control conditions, this potentiated elevation of intracellular Ca2+ was to a large extent dependent on extracellular Ca2+. In potentiated cells, muscarinic stimulation also activated a rapid Mn2+ entry. By using known organic and inorganic blockers of cation channels, this influx pathway was easily separated from the known Ca2+ influx pathways, the store-operated pathway and the voltage-gated Ca2+ channels. In addition to the Ca2+ influx, both IP3 production and Ca2+ release were also enhanced during the potentiated response. The results suggest that a small increase in intracellular Ca2+ amplifies the muscarinic Ca2+ response at several stages, most notably by unravelling an apparently novel receptor-activated influx pathway. (C) 2004 Elsevier Ltd. All rights reserved.