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E-Conference: Defining Calcium Entry Signals

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Calcium entry at physiological agonist concentrations

4 June 2004

Trevor Shuttleworth

Nobody who knows our work will be surprised when I say that I completely agree with Mike's point emphasizing the importance of determining which mechanism(s) for Ca2+ entry operate at physiological agonist concentrations. However, I would just make a a couple of isolated comments.

RE: In response to the question raised that "studies on cloned cell lines have identified a number of putative entry signals such as DAG, IP3, arachidonic acid, store emptying etc, but what is the evidence that any of these actually play a role in primary cells?". We have shown the presence of the ARC channels in parotid acinar cells (from both mouse and human), and demonstrated their crucial role in Ca2+ entry at low agonist (carbachol) concentrations.

RE: The discussion regarding the mechanism for the entry of Ca2+ necessary to maintain oscillations occurs with a minimal depletion of the internal store seeming to rule out a role for a store-operated signaling mechanism. Also, the point made that "perhaps the earliest Ca2+ response at physiological agonist concentrations is an increase in entry that then sets the stage for Ca2+ release". We, of course, agree and have made this same point repeatedly, ourselves. However, our data on Ca2+ entry during oscillations in HEK cells are not consistent with the "revised conformational coupling" model proposed. In these cells, although the muscarinic receptors are coupled, as usual, to PLC, the entry of Ca2+ is independent of PLC activity. It is, instead, entirely dependent on the generation of arachidonic acid which, in the HEK cells at least, is exclusively via a cPLA2. This enzyme is also coupled to the activation of the muscarinic receptors, but a way that is separate, but parallel, to PLC. Of course, different cells may operate differently, and we don't have to consider that there is just one option. The real point I am trying to make here is that although we usually talk about PLC- coupled receptors, it is important to remember that such receptors may not couple exclusively to this enzyme, and other independent signaling pathways may be activated.

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