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Journal of Physiology (2002), 544.1, p. 1
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.027151

SOCs - store-operated channels in vascular smooth muscle?

David J. Beech

Email: d.j.beech{at}leeds.ac.uk

Unravelling the mechanisms of noradrenaline's vasoconstrictor action is a fascinating business, and an important example of the rich texture of signalling within smooth muscle cells. Noradrenaline's stimulation of ₁-adrenoceptors sets off complex signalling cascades that act to initiate and maintain vascular smooth muscle contraction. One early discovery was that noradrenaline releases Ca²⁺ from intracellular stores. Whether this is a graded, all-or-nothing or oscillatory response, the stores must at some stage refill. This can occur partly by uptake of cytosolic Ca²⁺ but, because released Ca²⁺ is extruded from the cell, Ca²⁺ replenishment from the extracellular fluid is also necessary. Voltage-gated Ca²⁺ channels can contribute, but vascular smooth muscle cells - like other cell types - would also seem to have specialised Ca²⁺ channels for this function. Twenty-one years ago in The Journal of Physiology, Casteels & Droogmans published results obtained using ⁴⁵Ca²⁺ as a tracer. Depletion of intracellular stores stimulated the rate of ⁴⁵Ca²⁺ uptake from the extracellular solution. The pathway appeared to be tightly coupled to stores because the Ca²⁺ uptake failed to cause contraction. It was resistant to conventional Ca²⁺ antagonists and inhibited by K⁺-induced depolarisation. Manganese ions blocked the pathway. These data were the first suggesting the existence of a store-operated channel (SOC) that opens to allow Ca²⁺ entry when Ca²⁺ stores deplete.

The evidence for SOCs in vascular smooth muscle is good. Blockade of Ca²⁺ reuptake into stores by inhibitors (e.g. cyclopiazonic acid) of the store's Ca²⁺-ATPase (SERCA) or chelation of Ca²⁺ leaking from stores by BAPTA both cause store depletion while circumventing complexities of -adrenoceptor-mediated signalling. Both also activate Ca²⁺-permeable non-selective cationic channels in the plasma membrane of aortic and portal vein smooth muscle cells (Trepakova et al. 2000; Albert & Large, 2002a). The portal vein channels differ from those in aorta, for example showing greater Ca²⁺-selectivity, but neither is as Ca²⁺-selective as the calcium-release-activated Ca²⁺ (CRAC) channels of lymphocytes. Nevertheless, both vascular channels are coupled to store depletion. SERCA's fundamental role in intracellular Ca²⁺ handling and in the superficial buffer barrier of vascular smooth muscle can complicate experiments with SERCA inhibitors, as can background Ca²⁺-flux pathways. The use of manganese flux as an indicator of SOC activity may be undermined by manganese block of SOCs. But, by-and-large, such experiments have supported the existence of SOCs in vascular smooth muscle. Further evidence has also emerged. The SOCs of aortic myocytes are activated by calcium influx factor (CIF), a substance of unknown chemical identity released from store-depleted - but not control - platelets (Trepakova et al. 2000). There is also TRPC1 protein at the plasma membrane of vascular smooth muscle cells. TRPC1 has sequence homology to voltage-gated ion channel -subunits. Nine independent laboratories now have data showing it is a functional component of SOCs. A TRPC1 peptide-specific antibody attenuates SOC-mediated Ca²⁺ entry in vascular smooth muscle (Xu & Beech, 2001). Intriguingly, in platelets, TRPC1 co-immunoprecipitates with inositol trisphosphate receptor, but only when stores are depleted (Rosado & Sage, 2001). Therefore, molecular elements necessary for SOCs are present and active in vascular smooth muscle.

In this issue of The Journal of Physiology, Albert & Large (2002b) report patch-clamp data on the mechanism coupling ₁-adrenoceptors to SOCs in portal vein smooth muscle cells. They provide compelling evidence that SOCs can be activated independently of store depletion. In cell-attached patches noradrenaline activates channels that are biophysically very similar to those activated by cyclopiazonic acid - i.e. they both appear to activate the same SOC. Strikingly, SOC activation by noradrenaline, cyclopiazonic acid or BAPTA is prevented by protein kinase C inhibitors. In excised outside-out patches, noradrenaline and protein kinase C activators stimulate SOCs - but cyclopiazonic acid has no effect, as if the store-depletion mechanism is absent. Therefore, although noradrenaline depletes Ca²⁺ stores it seems it can also activate the portal vein SOCs independently of store-depletion, via a classical phospholipase C-diacylglycerol-protein kinase C pathway. The physiological importance of this effect compared with the store-operated mechanism will need to be worked out, as will the apparent dual role of protein kinase C in the store-independent and -dependent pathways. We can look forward to more intrigue to come.

Albert, A. P. & Large, W. A. (2002a). Journal of Physiology 538, 717-728.	[Abstract/Full Text]
Albert, A. P. & Large, W. A. (2002b).Journal of Physiology 544, 113-125.	[Abstract/Full Text]
Casteels, R. & Droogmans, G. (1981).Journal of Physiology 317, 263-279	[Abstract]
Rosado, J. A. & Sage, S. O. (2001).Biochemical Journal 356, 191-198.	[Medline]
Trepakova, E. S., Csutora, P., Hunton, D. L., Marchase, R. B., Cohen, R.A. & Bolotina, V. M. (2000). Journal of Biological Chemistry 275, 26158-26163.	[Abstract/Full Text]
Xu, S. Z. & Beech, D. J. (2001).Circulation Research 88, 84-87.	[Abstract/Full Text]

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This Article Abstract Full Text (PDF) All Versions of this Article: 544/1/1    most recent 2002.027151v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Beech, D. J. Search for Related Content PubMed PubMed Citation Articles by Beech, D. J. Related Collections Perspectives