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E-Conference: Defining Calcium Entry Signals

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Calcium entry regulation of calcium release

4 June 2004

Randen L. Patterson

The importance of calcium entry in regulation and control of calcium oscillations has been one of considerable debate. Many groups have demonstrated that modulation of calcium entry can change the frequency and amplitude of agonist-mediated calcium oscillations, which are key for processes such as gene expression.

These experiments support the existence of functional IP3 receptors in extremely close opposition to the plasma membrane, generating CICR, which would allow these local signals to generate and control global signals, a reasonable argument.

The opposition to these observations is from experiments demonstrating increased agonist concentration can ablate the need for external calcium entry. Although for many years I myself have used the removal of external calcium during experiments to separate calcium release from calcium entry, this experimental paradigm does not model physiological conditions.

Cells are never exposed to low, or zero calcium. Therefore, although oscillations can occur in the absence of calcium entry, this does not happen in physiology. Furthermore, the removal of external calcium, although commented on little in the literature, can actually obscure the interplay between calcium release and entry.

During the last 3 years, I have been examining proteins from a yeast-2-hybrid screen with the IP3-receptor for their functional effects on calcium release and entry. I used the experimental paradigm of overexpressing these proteins in PC12 cells, and then testing for a functional output by first adding agonist in the absence of external calcium to observe calcium release, and then adding back calcium to look for changes in calcium entry. What I failed to realize until recently, is that any protein that was modulating calcium entry "coupled" to calcium release or visa versa would not be represented.

A third experiment must be added to this paradigm for it to work, which is merely adding agonist in the presence of calcium to observe the integrated calcium signal.

I think it is safe to say, we have all seen phenomena that occur only when calcium is removed from the external media, or performed experiments that were sensitive to an order of operation. These observations should not be removed from manuscripts, rather they should be highlighted. We know so little about the mechanisms coordinating calcium release and entry events, any reproducible data is important to the community for deciphering these complex processes, and should be published.

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