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E-Conference: Defining Calcium Entry Signals

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

11 June 2004

Kenneth L. Byron

I agree with Victoria that there are distinct channels that mediate receptor-operated Ca2+ entry and store-operated (a.k.a. capacitative) Ca2+ entry. Several years ago, Colin Taylor and I provided evidence, using fura-2 fluorescence techniques, that vasopressin receptor activation leads to divalent cation entry via a noncapacitative Ca2+ entry (NCCE) pathway in A7r5 vascular smooth muscle cells (1). The NCCE pathway was apparently activated in addition to capacitative entry (CCE) and had different divalent cation permeabilities than CCE. More recently, my lab has been using electrophysiological methods to examine cation currents in A7r5 cells and our results (soon to be published, I hope) are consistent with the fura-2 studies. We find that vasopressin activates at least three distinct non-selective cation currents. One of these is a store-operated current, which can also be activated by passive store depletion (e.g. with thapsigargin or internal BAPTA). The other two currents are not activated by store depletion, but robustly activated by vasopressin.

Victoria has already speculated on reasons for having such distinct mechanisms. One aspect that she didn’t elaborate on is the concentration-dependence for activation of these different pathways by agonists. It seems likely that we will find that different Ca2+ entry pathways are activated over different ranges of agonist concentration and may allow for a broader range of biological responses with varying agonist concentrations. I have argued previously (2) that vasopressin elicits very different Ca2+ signals at low (picomolar) versus high (nanomolar) concentrations and that these signals may in turn trigger different physiological responses (Ca2+ spiking at low [vasopressin] may produce rhythmic vasoconstriction, Ca2+ release and store-operated Ca2+ entry at high [vasopressin] may be involved in mitogenic stimulation). It will be very interesting to learn whether there are distinct structures within the cells that allow not only activation of these channels by distinct signaling cascades, but may also direct the entering Ca2+ to particular subcellular targets, thereby promoting a selective functional response depending on which complement of channels are activated at any given concentration of agonist.

1. Byron, K.L. and Taylor, C.W. (1995) Vasopressin stimulation of Ca2+ mobilization, two bivalent cation entry pathways, and Ca2+ efflux in A7r5 rat smooth muscle cells. J. Physiol. (London) 485: 455-468.
2. Byron, K.L. (1996) Vasopressin stimulates Ca2+ spiking activity in A7r5 vascular smooth muscle cells via activation of phospholipase A2. Circ. Res. 78: 813-820.

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