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E-Conference: Defining Calcium Entry Signals

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What are the mediators of the store-operated calcium influx pathway?

4 June 2004

Victoria M. Bolotina

I guess no one will be surprised if I will talk about the role of CIF, iPLA2 and lysophospholipids...but I am not going to repeat what we have recently described in our papers (Smani et al. 2003, 2004). What I want is to spark a discussion on what we presently know and what we don't know (but definitely want to know) about this pathway.

So, how much do we really know? When you are able to put several simple steps into a cascade of reactions that may connect depletion of the stores with activation of plasma membrane channels, you think it is a lot. But next you start to ask specific questions about each individual step, and you realize how little we presently know, and how much more work (not by one, but by many labs) will be required to generate a complete detailed picture of this "simple" pathway. I will start with mentioning only few questions that we have about major mediators of the pathway:

- CIF identity remains a major issue; not existence, but identity. I am sure there always will be some one who will continue doubting CIF existence, simply because we do not know yet what it is. The good news is that now we at least know what it does to activate SOC, which is a major relief to all of us working with CIF model, and a great stimulus to keep us going in this direction.

- Ca2+-independent phospholipase A2 (iPLA2) appeared to be a perfect link that accommodates major requirements (and experimental observations) in store-operated pathway, but do we know everything about how it works? No, many important features of iPLA2 remain poorly understood. For example, how CaM binds to this protein, and what molecular interactions are crucial for its displacement? We have accumulating evidence that its binding and unbinding does not follow the same pattern, and is much more complex than in other CaM-binding systems. The good news are that this complexity seems to meet the physiological requirements for activation of store-operated channels when CIF is present, and inactivation when CIF is gone, independently of whether Ca2+ is high or low (physiologically low, not 10mM BAPTA conditions). Further studies are needed to fully understand how this ON-OFF switch in store-operated pathway (and certainly its fine-tuning device) works in different cellular systems.

- Lysophospholipids emerged as a next important class of lipid second messengers. Which lysophospholipids are more effective and how they activate SOC? We don't know, and it will be great to find out. So far, we did not find any differences in LysoPC and LysoPI in activating store- operated channels (Ca2+ influx) in RBL cells (Ca2+ -SOC or CRAC-type) and in SMC (cat-SOC type). The most important fact is that it looks like both types of store-operated channels, SOC (Ca2+ selective SOC /CRAC and nonselective cation SOC, whether Reinhold likes this idea, or not) react identically on LysoPC and LysoPI. This further supports the idea that store-operated channels exist in different flavors with Ca2+ selectivity being the major (if not the only) variable, which is very important for adjustment of the pathway to the specific needs of different type of the cells.

- The most important characteristic that is common for all SOCs tested so far is that they are all operated via the same CIF -iPLA2-LysoPL pathway. The crucial role of iPLA2 in SOC activation has been already confirmed not only in RBL, Jurkat, SMC and platelets, but also in most recent studies by Prevarskaya et al (JBC, May 2004) in epithelial cells, and in several other pending studies that we will soon hear about. Isn't it exciting that there is a new simple pathway identified, which opens tremendous possibilities for moving forward in many different directions? But is this the only pathway that can connect SOC with the stores? We don't know... and I am sure there will be many different opinions on this question, which certainly will be interesting to discuss in this Forum. The truth is waiting to be discovered.

It would be great to hear different opinions and certainly questions about what else we all want to know.

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