E-Conference: Defining Calcium Entry Signals
The role of Ca2+ stores in activating Ca2+ entry:
4 June 2004
Victoria M. Bolotina
Indeed, are the changes in intracellular stores necessary or sufficient (or both) to activate Ca2+ entry?
This is a very good question, and the answers are... "Yes and No", which is one of many reasons why this pathway remains such a complicated and controversial issue for such a long time.
Physiologically depletion of the stores definitely provides a major trigger for activation of store-operated channel (SOC), and in this respect changes in Ca2+ stores are indeed necessary for activating Ca2+ entry. Refilling of the stores is also needed for termination of Ca2+ influx, and acceleration of CaATPase (SERCA)-dependent refilling indeed shuts down Ca2+ influx, as we (and others) have demonstrated as a mechanism for physiological effect of nitric oxide on Ca2+ influx in smooth muscle cells (SMC), platelets and other systems.
On the other hand, under experimental conditions, you do not necessarily need to deplete the stores-- you may activate the channels by affecting the pathway downstream from the stores. For example, in our new model in which iPLA2 is a crucial determinant of the pathway (Smani et al., Nature Cell Biology 2004), activation of Ca2+-independent phospholipase A2 (iPLA2) (by cell dialysis with 10 mM BAPTA, by calmodulin (CaM) displacement with CMZ or CaM inhibitory peptide, or by something else that is yet to be determined) results in activation of SOC (and Ca2+ influx) that is identical to that activated by depletion of the stores with thapsigargin (TG). In these cases, depletion of the stores was not necessary for activation of SOC and Ca2+ influx, because a short cut in this pathway was used. Can short cuts be present and used under some physiological /pathological conditions? We don't know, and this is something very interesting to look for in different cellular systems.
Is depletion of the stores sufficient for activation of SOC? In most cases yes, but in some cases it may not be enough. For example, inhibition of iPLA2 (disrupting the pathway), or simple down regulation of iPLA2 excitability (if it would be technically possible), makes depletion of the stores insufficient for activation of SOC. This disruption can be reversed by application of iPLA2 product, lysophospholipids, which we have shown to activate SOC channels even when iPLA2 is inhibited. Thus, regulation of iPLA2 activity can serve as a major on-off switch (as well as a tuning device) for the whole pathway that connects depletion of the stores with activation of SOC and Ca2+ influx. The prediction may be that in experimental conditions, direct activation of iPLA2 (by any means) will produce activation of SOC without depletion of the stores, and inhibition of iPLA2 will make store depletion insufficient for SOC activation.
Also, one should consider production and degradation of Lysophospholipids as another store-independent way for regulation of SOC activity. It is important to emphasize, that we presently know nothing about how lysophospholipid products of iPLA2 activate SOC. Activation may occur as a result of their direct interaction, as well as through some other still unidentified membrane delimited machinery, which awaits its discovery.
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