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E-Conference: Defining Calcium Entry Signals

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Calcium entry mechanisms

15 June 2004

Trevor Shuttleworth

Mike –Re. your comment that I had recently proposed that Ca2+ may be "contributing directly to the spike".

Just to clarify, if I implied that the Ca2+ entering actually formed part of the increase in Ca2+ associated with the spike, then I apologize. That is certainly not what I meant.

Rather, we have always believed that the Ca2+ spike is entirely a result of Ca2+ released from the stores (an exception may be T lymphocytes where, I understand, Rich Lewis has argued for a direct contribution of Ca2+ to the Ca2+ spike).

The evidence we had, indicated that Ca2+ entry did not seem to be modulating oscillation frequency by any detectible influence on the rate of store refilling. This implied an effect on the release process.

We thought that this probably resulted from the entering Ca2+ acting as a co- agonist with IP3 at the IP3 receptors to trigger release, and often stated as much.

However, as you pointed out to me (I think) at the Liverpool meeting last year, there are problems with this interpretation, and we agree with you. Consequently, we have begun thinking about possible alternative mechanisms – although, based on our evidence, I still believe that we should be focusing on an effect on release from the stores.

By the way, in a recent collaboration with James Sneyd (PNAS 101: 1392-1396) he came up with a model that suggested that the "critical parameter" for the effect of entry on oscillation frequency was the TOTAL Ca2+ load in the cell (not specifically in the stores), and how this was influenced by the balance between influx and efflux across the plasma membrane. We are still struggling to work out what this may mean in a biological/physiological sense, and there are still some aspects that the model does not fully describe, but it has certainly given us something to think about!

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