Is there a role for store-operated calcium entry in vasoconstriction?
2001; American Physical Society; Volume: 280; Issue: 5 Linguagem: Inglês
10.1152/ajplung.2001.280.5.l866
ISSN1522-1504
Autores Tópico(s)Ion channel regulation and function
ResumoEDITORIAL FOCUS 3EDITORIAL FOCUSIs there a role for store-operated calcium entry in vasoconstriction?Troy StevensTroy Stevens Department of Pharmacology, University of South Alabama College of Medicine, Mobile, Alabama 36688Published Online:01 May 2001https://doi.org/10.1152/ajplung.2001.280.5.L866MoreSectionsPDF (113 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat transitions in cytosolic calcium concentration ([Ca2+]i) represent an important physiological signal in cells (1). A rise in smooth muscle cell [Ca2+]i activates myosin light chain kinase, which promotes myosin light chain phosphorylation and actomyosin interaction. However, recent evidence has indicated that Ca2+-dependent signaling cascades are highly compartmentalized, suggesting that a nonspecific global rise in [Ca2+]i per se is insufficient to evoke a specific physiological outcome. For example, ionomycin-induced rises in global [Ca2+]i do not regulate membrane-delimited enzyme function as efficiently as Ca2+entry across the cell membrane (8, 10, 11, 22). Similarly, large-scale increases in [Ca2+]i do not always increase myosin light chain phosphorylation (13). These findings illustrate the importance of determining how compartmentalized Ca2+ signals regulate cell-specific function. In this issue of the American Journal of Physiology-Lung Cellular and Molecular Physiology, McDaniel et al. (24) address the Ca2+ source that is essential for Gq agonists to contract pulmonary arterioles.Resting [Ca2+]i is normally maintained near 100 nM, reflecting the constitutive balance of Ca2+ release from intracellular storage sites (e.g., endoplasmic reticulum and mitochondria), Ca2+ entry across the plasmalemma, Ca2+ reuptake into intracellular storage sites, and Ca2+ extrusion across the cell membrane (1). This low resting concentration can be rapidly increased after either Ca2+ release from intracellular organelles or direct entry across the cell membrane. Multiple Ca2+ release and entry mechanisms exist, although the functional significance of each pathway is cell-type specific.Ca2+ release in smooth muscle cells can be achieved by three distinct mechanisms, including activation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3] and ryanodine/cyclic ADP-ribose receptors (1). Ins(1,4,5)P 3-induced Ca2+ release is relatively well understood. Membrane receptors coupled to Gq proteins stimulate phospholipase C and generate Ins(1,4,5)P 3, which promotes Ca2+ release through Ins(1,4,5)P 3 receptors localized predominantly on the endoplasmic reticulum. Depletion of the Ins(1,4,5)P 3-accessible pool regulates Ca2+ entry across the plasmalemma through so-called store-operated Ca2+ (SOC) entry channels. Indeed, the open probability of SOC entry channels is regulated specifically by the endoplasmic reticulum Ca2+ concentration. A replete Ca2+ pool closes SOC entry channels, whereas depletion of the Ca2+ pool by Ins(1,4,5)P 3 activates plasmalemmal cation channels that increase [Ca2+]i(30).Despite the widespread significance of SOC entry, the molecular identity of SOC channels remains unclear (16). Transient receptor potential (Trp) gene products are the best candidates for SOC entry channels. The Drosophila melanogaster Trp gene was identified in 1989 (reviewed in Ref. 16) and was later determined to encode a retinal SOC entry channel. Since 1995, seven related mammalian homologs have been identified, several of which encode for SOC entry channels (at least Trp1, Trp2, Trp4, and Trp5) (16,36). Other Trp homologs, most notablyTrp3, directly interact with the Ins(1,4,5)P 3 receptor (4, 19,20). Although these findings suggest that individual Trp proteins exhibit unique regulatory properties, extrapolation of the findings to endogenously expressed Trp-containing channels is not evident. Functional Trp channels may be formed by cohesion of four distinct subunits that assemble as homo- or heteromultimers (2). The biophysical properties of individual Trp proteins that are overexpressed to presumably form homotetrameric channels differ substantially from the biophysical properties observed when different Trp proteins are overexpressed together and allowed to coassemble (23). These data suggest that the combination of Trp proteins expressed may partly determine whether the channels are store and/or receptor operated. Thus the expression pattern of Trp proteins may produce cell type-specific channels.Several agonists have been used to activate SOC entry and to examine Ca2+ entry through Trp channels. Thapsigargin is a plant alkaloid that inhibits sarco(endo)plasmic reticulum Ca2+-ATPase and causes the passive depletion of endoplasmic reticulum Ca2+ without the confounding influence of G proteins (33). Studies using thapsigargin and related compounds [e.g., 2,5′-di(tert-butyl)-1,4-benzohydroquinone, cyclopiazonic acid] illustrate that smooth muscle cells possess SOC entry pathways. However, a clear link between SOC entry and smooth muscle contraction has not been established (3, 14, 34), perhaps because thapsigargin stimulates endothelial production of nitric oxide (25). In vivo Gq agonists represent the prominent stimulus for activation of SOC entry. The α-adrenoreceptor is such a Gq-Ins(1,4,5)P 3-linked pathway that regulates the contractile status of blood vessels. However, studies to date have not clarified whether α-adrenergic agonists induce vasoconstriction through SOC entry channels (3) because Gq-linked pathways cause membrane depolarization and can activate voltage-gated Ca2+ channels that are thought to predominate in smooth muscle (5, 7).Activation of L-type Ca2+ channels has been clearly linked to pulmonary and systemic vasoconstriction. Membrane depolarization with high K+-containing physiological salt solutions rapidly activates these channels, increasing [Ca2+]i solely through Ca2+ entry across the plasmalemma. This effect is not limited to experimental preparations because physiological changes in Po 2 regulate resting membrane potential (32). Acute hypoxia inhibits voltage-dependent K+ channel activity and reversibly depolarizes the resting membrane potential sufficiently to activate Ca2+ entry, resulting in an approximate threefold elevation in [Ca2+]i (9, 29, 38). Consequently, hypoxia may cause vasoconstriction by acting directly on smooth muscle. L-type Ca2+ channels proved to be an effective pharmacological target for the treatment of systemic and, to some extent, pulmonary hypertension. However, in considering the possibility that α-adrenoreceptor agonists may increase [Ca2+]i through activation of either voltage-gated or store-operated Ca2+ channels, the source of Ca2+ responsible for vasoconstriction remains unclear.Indeed, it was this very problem that was addressed by McDaniel et al. (24). They found that although inhibition of the L-type Ca2+ channel abolished vasoconstriction induced by high-K+ buffer, nifedipine and verapamil only reduced the phenylephrine-induced contraction by 30%. These findings suggested that either Ca2+-independent mechanisms were evoked by the Gq agonist or that another Ca2+ source was required for phenylephrine to sustain a contraction. Recalcification experiments were performed to address this issue. Phenylephrine was applied in the absence of extracellular Ca2+ to initiate Ins(1,4,5)P 3-dependent Ca2+ release. Ca2+ was then readded to the extracellular buffer to initiate Ca2+ entry in the presence or absence of α-adrenoreceptor and L-type Ca2+ channel blockade. Under these experimental conditions, ∼30% of the vasoconstriction induced by phenylephrine was attributable to SOC entry.Efforts to characterize the SOC entry pathway revealed that store depletion increased [Ca2+]i in cultured smooth muscle cells and also activated a cationic current in the whole cell voltage-clamp configuration. In patch-clamp experiments, the holding potential was 0 mV to inactivate L-type Ca2+channels. The cyclopiazonic acid-activated current (I SOC) was large (approximately −500 pA at −80 mV), reversed near 0 mV, was linear (e.g., was not inwardly rectifying), and was inhibited by Ni2+ (1 mM) and La3+ (50 μM). These data resemble the nonselective currents observed in response to Ca2+ store depletion in other cell types and do not resemble Ca2+ release-activated Ca2+ current (I CRAC) found initially in mast cells and lymphocytes. I CRAC is very small (less than approximately −50 pA at −80 mV), exhibits a positive reversal potential (approximately +40 mV), and is strongly inwardly rectifying. Highly Ca2+-selective channels possess an anomalous mole fraction effect where monovalent cations are readily conducted in the absence of Ca2+ but excluded in the presence of low Ca2+ concentrations (15, 17, 21,37). In this regard, both I CRAC and voltage-gated Ca2+ channels exhibit anomalous mole fraction behavior. The issue of ion selectivity is critical to the development of an overall understanding of the apparent myocyte Ca2+entry pathway(s) because it is likely that the molecular makeup of Ca2+-nonselective and -selective store-operated channels is distinct. The findings of McDaniel et al. (24) suggest that at least one smooth muscle cell SOC entry pathway is nonselective, generally consistent with the recent work of Trepakova et al. (35).McDaniel et al. (24) report expression of Trp1, -2, -4, -5, and -6 in isolated myocytes. These findings implicate Trp proteins in myocyte I SOC but, at the present time, do not provide direct evidence for which channel or combination of subunits contributes to the observed nonselective current. Ion selectivity of Trp proteins is still largely unresolved. Of the channels examined to date, only Trp4 and Trp5 appear to encode for a Ca2+-selective channel (26-28, 37), and even this finding has been inconsistent (31). When evaluated, nonselective currents have generally been observed after overexpression of Trp1 (39) and Trp3 (18). However, my laboratory (Brough G, Wu S, Cioffi D, Moore T, Li M, Dean N, and Stevens T, unpublished observations) recently examined the contribution of endogenously expressed Trp1 to a Ca2+-selective I SOC that resemblesI CRAC (12). Antisense inhibition of Trp1 reduced this Ca2+-selective current by 50% and did not left shift the reversal potential from +40 mV. These findings were interpreted to suggest that although Trp1 may form a structural subunit of a Ca2+-selective store-operated channel, it is likely not required to establish the Ca2+ selectivity of the channel. Thus although it is evident that cation entry occurs through Trp proteins in response to Ca2+ store depletion, the endogenous makeup of these channels and their contribution(s) to nonselective cation and/or Ca2+-selective currents are unclear.Overall, the findings presented by McDaniel et al. (24) address an important question and underscore how little is known regarding the fundamental aspects of Ca2+ signaling in the control of vasoconstriction. As we continue to resolve the detail of signal transduction pathways, it will be critical to establish more specifically which Trp proteins coalesce to form functional channels and to determine how these channels generate nonselective versus Ca2+-selective currents. It will be equally important to discern how SOC entry pathways work in combination with L-type Ca2+ channels to uniformly or discretely regulate vascular tone. Resolution of these issues may result in the generation of novel antihypertensive pharmacotherapeutic agents directed against myocyte-specific, Trp-containing SOC entry channels.I thank Drs. I. F. McMurtry and M. Zhu for helpful comments in preparing this review.FOOTNOTESAddress for reprint requests and other correspondence: T. 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Pearce1 December 2001 | American Journal of Physiology-Cell Physiology, Vol. 281, No. 6 More from this issue > Volume 280Issue 5May 2001Pages L866-L869 Copyright & PermissionsCopyright © 2001 the American Physiological Societyhttps://doi.org/10.1152/ajplung.2001.280.5.L866PubMed11290509History Published online 1 May 2001 Published in print 1 May 2001 Metrics
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