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E-Conference: Defining Calcium Entry Signals

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Comments on cellular domains that contribute to calcium entry events

11 June 2004

Michael Berridge

I was pleased to see that Ken agrees with the need to consider physiological doses of agonist. This is a very important issue that cannot be over stressed.

In answer to the question of whether some of the alternative entry mechanisms (e.g. CIF, AA) impinge upon the conformational coupling (CC) mechanism, I doubt it. This does not mean that the do not play a role as I indicate in my answer to Trevor’s qiestion outlined above. It seems that these other entry signals act directly on channels so there is no need to suppose that they act through the CC mechanism.

The second question concerns the organisation of other components that function together with the CC mechanism. It is difficult to be precise about this. With regard to the IP3Rs, it is important to make a distinction between the coupled IP3Rs that occur in the junctional zone and the uncoupled IP3Rs that lie elsewhere on the ER. It is the positioning of the latter that are critical and, as Ken suggests, some of these may be situated close to downstream effectors well away from the cell surface. Indeed it is clear from various cell types that the initiation site where release begins is often located away from the cell surface. As pointed out by Indu Ambudkar, this spatial separation of entry and release is particularly evident in pancreatic acinar cells where entry occurs at the basal side while release occurs in the apical region. This relates to the question raised by Ken at the end of his comments, what is the relationship between entry at the junctional zone and the subsequent release? In the hypothesis I outlined in my comments, I proposed that the ER takes up the calcium that enters at the junctional zone. This Ca2+ can then tunnel throughout the ER network to increases the lumenal level of Ca2+ which in turn sensitizes all the uncoupled receptors so that they can release Ca2+ during each spike. A critical part of the hypothesis is the role that lumenal Ca2+ plays in sensitizing IP3Rs to set the stage for release to occur (see also my comments to Reinholt Penner).

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