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E-Conference: Defining Calcium Entry Signals

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Re: Randen's comments on defining channels

4 June 2004

Trevor Shuttleworth

I would have to take issue with a couple of the responses Randon has made to my original posting (but the this is what this all supposed to be about, right?)

1. "Electrophysiology (particularly whole-cell patching) can only provide the biophysical properties of the channel, not the molecular identity". This is my point precisely. In the absence of any clear molecular clues, our best bet is to precisely characterize the biophysical fingerprint of the channel. At least that way, if any molecular candidate is proposed we have the ability to compare the molecular properties of the candidate with those of the endogenous channels in a preciuse way. It exactly this kind of analysis that leads me to have a problem with the "TRPC argument". There is simply no way that "fluorescent calcium entry" recordings can provide such a fingerprint.

2. "In addition, even if single channel recordings could be taken of these channels, it is performed in the ABSENCE of every other channel. Calcium signals are integrated into the receptor response, and have inputs and outputs to and from other ion channels. Therefore, study of single channels, although important to understanding channel properties, is a poor system for determining the "behavior" of these channels, or their role in cellular physiology." I agree, but you are talking about the behavior and role of the channel in signaling. Whilst I would be the first to agree that these are essential components of our understanding of the channel, I do not agree that they offer much to help in its identification.

3. "Secondly, what is the definition of calcium selective channels anyways?" I think I may have misled you here. I was using the terms "Ca2+-selective" and "non-selective" in relation to the relative permeabilities of Ca2+ versus monovalent cations (i.e. Na+ in normal physiological conditions). I would say that channels such as CRAC, ARC, and the ECaCs (TRPV5 and 6) are clearly highly Ca2+-selective (pCa2+:pNa+ >>100). In contrast, many of the non-selective conductances seen, for example, in smooth muscle cells, as well as most of the reports on TRPCs indicate pCa2+:pNa+ <10. Although these will conduct Ca2+ and may make a contribution to overall Ca2+ entry, I would say a reasonable classification for these is "non-selective cation channels". Personally, I find the Ba2+/Sr2+ story for most entry pathways very confusing and not very informative.

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