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E-Conference: Defining Calcium Entry Signals

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Distinctions between receptor-operated and store-operated Ca2+ entry:

4 June 2004

Victoria M. Bolotina

Do receptors activate distinct Ca2+ entry events from those stimulated by store-emptying? Are the Ca2+ entry events activated by receptors and emptied stores independent or integrated?

Here is another point of major confusion. Many do not discriminate receptor- and store-operated pathways simply because both are triggered by agonist-induced activation of the same receptors, and result in entry of the same Ca2+ ions into the cell.

I strongly believe receptor-operated and store-operated pathways are independent, and may be viewed as separate and very specific branches of a global receptor-triggered Ca2+ influx machinery. These pathways may have one starting point (such as receptor activation), but definitely present separate signaling cascades that involve different reactions leading to activation of different ion channels. They can function independently of each other, but they certainly may be (and most probably are) integrated into more complex interactions. The nature of these interactions (their cross-talk) may depend on the physiological requirements of specific cell types. It may strongly depend on whether two signaling cascades are spatially co-localized, or separated into different structural/functional compartments (domains).

For example, G proteins, IP3, PIP2, DAG (and any other immediate products) may determine a short signaling pathway (co-localized with the receptor), which is designed to activate specific receptor-operated channels (many belonging to TRP family). This "short" pathway co-localized with the receptors could be called a receptor-operated pathway. But the same receptor may trigger another cascade of reactions: IP3 can travel to ER, and release Ca2+, producing store depletion (partial or global, localized of diffuse is still to be determined). This may be a crucial stimulus for production of another major signal (like CIF), which may be released in totally different cellular compartments that are restricted to another plasma membrane-delimited signaling domain, which we believe includes iPLA2 and store-operated channels.

There certainly may be other major components that eventually will be determined and placed in the same signaling cascade/domain. SOC may never see IP3 (or any other immediate products released in the vicinity of the receptors), but through a "long" and complex pathway (going through the stores), SOC activation will still physiologically depend on agonist-induced IP3 production.

For me, the term "receptor-operated" Ca2+ influx means that specific Ca2+-conducting channels (not SOC) are closely associated with the receptor, and are regulated by its immediate products.

The term "store-operated" points to the fact that the signal goes much further, and downstream there is yet another major triggering event (store-depletion) that is needed to activate a specific type of Ca2+ influx channels (store-operated channels, or SOC), which may be located far away from the receptors.

Why did nature create several different and independent cascades that may be triggered by the same receptor, but then diverge into different pathways, which eventually lead to the same event, Ca2+ influx? The answer is simple -- nature needs diversity and precision. We all know that Ca2+ signaling is not the same when calcium enters through different and highly specialized channels localized to different structural/functional domains. So, it is important to discriminate between store-operated and receptor-operated Ca2+ influx, (as well as many other type of global Ca2+ entry mechanism).

First, we need to get a clear picture of how each of them may work independently of all others. And only then we can ask the next question, how those pathways may talk to each other? This is the next level of system complexity, which is hard to address correctly without first obtaining a total clarity on how each individual pathway works. Right now,we are still at the level of arguing "whether store-operated and receptor-operated Ca2+ influx pathways are the same or different", and each of us has a different opinion. My opinion is only an invitation for the discussion in this Forum...

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