Muscarinic receptor activated Ca2+ channels in non-excitable cells

We have provided preliminary characterization of a single channel Ca2+ conductance in CHO cells. We have demonstrated that the channel conducts Ca2+, is regulated by m5 receptors, is voltage-independent, has an extremely low conductance, and is second messenger-independent. This channel may be the receptor-operated channel required for downstream activation of several signaling events. It is not known what other cell types express the channel or if it is one of a larger group of related channels. It seems likely that Ca2+ influx-dependent signaling pathways, activated by the muscarinic m5 receptor, would utilize a plasma membrane resident Ca2+ channel to provide a steady source of Ca2+ from outside the cell. The transient nature of IP3-activated increases in intracellular Ca2+ make it an unlikely source of the sustained Ca2+ rise required for phospholipase regulation. This is especially surprising, since levels of intracellular Ca2+ achieved from the release of intracellular Ca2+ stores can be at least one order of magnitude higher than those achieved from extracellular influx (Berridge, 1993). The phospholipase A2 and phospholipase D involved in muscarinic receptor-mediated signaling have not been purified or cloned. It is possible that receptor-activated and Ca2+ influx-dependent phospholipases are integral membrane proteins located adjacent to both receptors and channels. The phospholipases may also translocate to the membrane following activation where they would gain access to the continuous Ca2+ flow. Purification and cloning of this and other related channels should provide better insight into their role in cell signaling.