Copyright © 2005, European Society of Cardiology
Non-capacitative calcium entry–Extension of the possibilities for calcium entry in vascular tissue
University of Rostock, Institute of Physiology, PSF 100888, D-18055 Rostock, Germany
* Corresponding author. Tel.: +49 381 4948016; fax: +49 381 4948002. Email address: rudolf.schubert{at}medizin.uni-rostock.de
Received 18 July 2005; accepted 25 July 2005
See article by Thomas et al. [5] (pages 56–64) in this issue.
The functional state of blood vessels is regulated by the calcium sensitivity of the contractile elements and the intracellular calcium concentration. The latter is determined by the balance between the activity of calcium sources (influx from the extracellular space and release from intracellular stores), the activity of calcium sinks (extrusion to the extracellular space and sequestration into intracellular stores), and the capacity of calcium buffers. Contractile reactions of blood vessels are depressed considerably after removal of extracellular calcium ions, emphasizing the importance of calcium entry for vessel contractility. Classically, voltage-operated calcium influx via L-type calcium channels had been assigned a leading role in calcium entry. However, a considerable number of contractile reactions have been shown to be resistant or only partly affected by specific inhibitors of voltage-operated calcium channels. Thus, voltage-independent calcium entry must contribute to vessel contractility. Indeed, several such mechanisms have been identified in different cell types [1–3], including smooth muscle [4]: 1) receptor-operated calcium entry, activated by direct binding of an external ligand to the channel; 2) store-operated or capacitative calcium entry (CCE), activated by calcium release from intracellular stores or, more precisely, by the degree of store depletion; 3) non-store-operated or non-capacitative calcium entry (non-CCE), activated independently of store depletion. In the past, the latter was often termed receptor-operated calcium entry. However, in view of the fact that all calcium entry mechanisms can be activated by agonist-receptor interaction, this term does not have much discriminatory power. Non-CCE is also designated second messenger-operated calcium entry because in most cases the common motif is its activation by second messengers following G-protein-mediated activation of phospholipase C (PLC) [2,3]. The existence of such a variety of calcium entry mechanisms is the basis for the diversity of patterns of calcium signalling in response to cell stimulation. However, the understanding of the functional role of non-CCE in vascular tissue is still limited, mainly because studies on intact vessel preparations are scarce.
It is the merit of the study by Thomas et al. [5] published in this issue of Cardiovascular Research to provide new evidence for the contribution of non-CCE to arterial contractions. The authors show that sphingosylphosphorylcholine (SPC) is a powerful vasoconstrictor of rat small intrapulmonary arteries. The Rho kinase inhibitor Y-27632 reduced SPC-induced contractions of intact vessels considerably and abolished calcium sensitization of permeabilized vessels. SPC-induced contractions were accompanied by an increase of the intracellular calcium concentration. Removal of extracellular calcium ions reduced the SPC-induced contraction and abolished the SPC-induced increase of the intracellular calcium concentration, pointing to an important role of calcium entry in SPC-induced responses. However, diltiazem, a blocker of L-type calcium channels, had almost no effect on SPC-induced contraction. In contrast, this contraction was reduced considerably by La3+ and 2-APB, putative inhibitors of CCE. In addition, 2-APB abolished the SPC-induced increase in the intracellular calcium concentration. Surprisingly, the SPC-induced contraction was not associated with a fast, transient increase of the intracellular calcium concentration typical for IP3-mediated calcium release and was not affected by pertussis toxin, a G-protein inhibitor, and U73122 [GenBank] , a PLC inhibitor. After activation of CCE by completely emptying intracellular stores with thapsigargin, the SPC-induced increase in the intracellular calcium concentration was unchanged. Thus, a calcium entry pathway seems to be involved in SPC-induced contractions of rat small intrapulmonary arteries that does not depend on emptying of PLC/IP3- or thapsigargin-sensitive intracellular stores, i.e. it is a non-CCE pathway but it is sensitive to the CCE inhibitors La3+ and 2-APB.
Along with the evidence for the contribution of non-CCE to arterial contractions, the study by Thomas et al. [5] published in this issue of Cardiovascular Research points to several additional, important issues. Firstly, the vasoactive substance investigated in this study, SPC, is a member of a group of membrane-derived lysophospholipids that have only recently gained more and more interest and seem to be important endogenous modulators of cardiovascular function in health and disease [6,7]. Secondly, the non-CCE postulated to play an important role in SPC-induced contractions in rat small intrapulmonary arteries coexists with CCE in these vessels [8]. However, it is still not clear how CCE and non-CCE calcium entry pathways are orchestrated. Recently, it was shown that reciprocal regulation of CCE and non-CCE is achieved by their separate activation at different levels of agonist concentration [1]. Thus, at low concentrations non-CCE was the main calcium entry mechanism, but at high concentrations the depletion of intracellular stores leads to activation of CCE, and the subsequent strong and sustained increase in intracellular calcium concentration results in a calcineurin-mediated inhibition of non-CCE. Alternatively, it was demonstrated that divergence within a PLC-coupled signalling cascade leads to a reciprocal regulation of non-CCE and CCE, i.e. to a simultaneous activation of the former and an inhibition of the latter [9]. In contrast, in the study by Thomas et al. [5], non-CCE was not coupled to PLC. In addition, the SPC-induced effect was sensitive to La3+ and 2-APB, agents that previously had been shown to inhibit CCE in the same vessels [8]. This may indicate that the distal elements of the signalling cascades leading to activation of CCE and non-CCE are closely related, as suggested recently in a functional study on rat renal cortical interlobular arteries [10]. Indeed, the division into CCE and non-CCE is based on the mechanisms activating these calcium entry pathways. Yet, the underlying conductances may be quite similar. Although the molecular identity of the channels responsible for CCE and non-CCE has not been established, TRP channels have been intensively discussed [4,11,12]. The observed differences in particular properties of the CCE and non-CCE conductances may be due to heteromultimer formation with different combinations of members of the TRP superfamily [2,4]. Thus, the study by Thomas et al. [5] provides evidence that CCE and non-CCE may also be orchestrated by convergence of separate signalling cascades.
A third important issue is that the signalling cascades mediating the activation of non-CCE in intact vessel preparations are largely unknown. Several second messengers have been suggested to activate non-CCE in different cell types [2,4]. Thus, Rho kinase has been proposed to mediate non-CCE induced by histamine and metacholine in guinea-pig trachea [13]. This idea is consistent with the finding of Thomas et al. [5] showing the involvement of Rho kinase in SPC-induced contractions. Interestingly, a recent study by another group demonstrated that the 5-HT-induced non-CCE in the same vessel is mediated by arachidonic acid [14]. Since arachidonic acid is able to activate Rho kinase in vascular smooth muscle [15], this finding supports the idea of an important role of a Rho kinase cascade for the activation of non-CCE in vascular tissues. However, observations in A7r5 cells demonstrated that the arachidonic acid-coupled activation of non-CCE was mediated by NO [9], pointing to the possible existence of multiple pathways for the activation of vascular non-CCE. Thus, there are still many open questions concerning the mechanism(s) of activation of non-CCE in vascular tissues. But this is not only a challenge for basic science. The development of selective inhibitors of non-CCE could provide potential therapeutic tools for vessels, as well as for other tissues, where calcium entry is dominated by non-CCE.
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 Top References |
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- Shuttleworth T.J., Thompson J.L., Mignen O. ARC channels: A novel pathway for receptor-activated calcium entry. Physiology (Bethesda) (2004) 19:355–361.[CrossRef][Medline]
- Bird G.S., Aziz O., Lievremont J.P., Wedel B.J., Trebak M., Vazquez G., et al. Mechanisms of phospholipase C-regulated calcium entry. Current Molecular Medicine (2004) 4:291–301.[CrossRef][Web of Science][Medline]
- Parekh A.B., Putney J.W. Jr. Store-operated calcium channels. Physiological Reviews (2005) 85:757–810.
[Abstract/Free Full Text] - McFadzean I., Gibson A. The developing relationship between receptor-operated and store-operated calcium channels in smooth muscle. British Journal of Pharmacology (2002) 135:1–13.[CrossRef][Web of Science][Medline]
- Thomas G.D., Snetkov V.A., Patel R., Leach R.M., Aaronson P.I., Ward J.P.T. Sphingosylphosphorylcholine-induced vasoconstriction of pulmonary artery: Activation of non-store-operated Ca2+ entry. Cardiovascular Research (2005) 68:56–64.
[Abstract/Free Full Text] - Ohmori T., Yatomi Y., Osada M., Kazama F., Takafuta T., Ikeda H., et al. Sphingosine 1-phosphate induces contraction of coronary artery smooth muscle cells via S1P2. Cardiovascular Research (2003) 58:170–177.
[Abstract/Free Full Text] - Alewijnse A.E., Peters S.L., Michel M.C. Cardiovascular effects of sphingosine-1-phosphate and other sphingomyelin metabolites. British Journal of Pharmacology (2004) 143:666–684.[CrossRef][Web of Science][Medline]
- Snetkov V.A., Aaronson P.I., Ward J.P., Knock G.A., Robertson T.P. Capacitative calcium entry as a pulmonary specific vasoconstrictor mechanism in small muscular arteries of the rat. British Journal of Pharmacology (2003) 140:97–106.[CrossRef][Web of Science][Medline]
- Moneer Z., Dyer J.L., Taylor C.W. Nitric oxide co-ordinates the activities of the capacitative and non-capacitative Ca2+-entry pathways regulated by vasopressin. Biochemical Journal (2003) 370:439–448.[CrossRef][Web of Science][Medline]
- Facemire C.S., Arendshorst W.J. Calmodulin mediates norepinephrine-induced receptor-operated calcium entry in preglomerular resistance arteries. American Journal of Physiology. Renal Physiology (2005) 289:F127–F136.
[Abstract/Free Full Text] - Inoue R., Mori Y. Molecular candidates for capacitative and non-capacitative Ca2+ entry in smooth muscle. Novartis Foundation Symposium (2002) 246:81–90.[Medline]
- Beech D.J., Muraki K., Flemming R. Non-selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP. Journal of Physiology (2004) 559:685–706.
[Abstract/Free Full Text] - Ito S., Kume H., Yamaki K., Katoh H., Honjo H., Kodama I., et al. Regulation of capacitative and noncapacitative receptor-operated Ca2+ entry by rho-kinase in tracheal smooth muscle. American Journal of Respiratory Cell and Molecular Biology (2002) 26:491–498.
[Abstract/Free Full Text] - Guibert C., Marthan R., Savineau J.P. 5-HT induces an arachidonic acid-sensitive calcium influx in rat small intrapulmonary artery. American Journal of Physiology. Lung Cellular and Molecular Physiology (2004) 286:L1228–L1236.
[Abstract/Free Full Text] - Pfitzer G. Invited review: Regulation of myosin phosphorylation in smooth muscle. Journal of Applied Physiology (2001) 91:497–503.
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