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Capacitative calcium entry: a central role in hypoxic pulmonary vasoconstriction?

2005; American Physical Society; Volume: 289; Issue: 1 Linguagem: Inglês

10.1152/ajplung.00101.2005

1522-1504

Jeremy Ward, Tom P. Robertson, Philip I. Aaronson,

Ion channel regulation and function

EDITORIAL FOCUSCapacitative calcium entry: a central role in hypoxic pulmonary vasoconstriction?Jeremy P. T. Ward, Tom P. Robertson, and Philip I. AaronsonJeremy P. T. Ward, Tom P. Robertson, and Philip I. AaronsonPublished Online:01 Jul 2005https://doi.org/10.1152/ajplung.00101.2005MoreFiguresReferencesRelatedInformationSectionsGRANTSAUTHOR NOTESPDF (51 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat it is known that hypoxic pulmonary vasoconstriction (HPV) requires an elevation in cytosolic [Ca2+] ([Ca2+]i) of pulmonary arterial smooth muscle (PASM), and numerous studies in both isolated PASM cells and arteries have shown that physiological hypoxia elicits a sustained increase in [Ca2+]i, sometimes preceded by a transient rise (2, 6, 28–30, 32, 39, 47). There is strong evidence that this involves Ca2+ entry across the cell membrane, as removal of extracellular Ca2+ or blockade of Ca2+ entry tends to abolish HPV and at least the sustained elevation in [Ca2+]i (6, 17, 19, 30, 32, 39). Currently, the most widely held hypothesis is that this Ca2+ entry is mediated via voltage-dependent L-type channels, as a result of hypoxia-induced inhibition of K+ channels and consequent depolarization (1, 23, 46). The evidence underlying this hypothesis is convincing, as many studies have reported that L-type channel blockers suppress HPV and/or the rise in [Ca2+]i (7, 17, 19, 32, 37, 39), and hypoxia has been shown to inhibit K+ channels and cause depolarization in both pulmonary artery and PASM cells (2, 14, 23–25, 49).However, the K+ channel hypothesis is not unassailable, as some reports have shown either no or only partial block of HPV with L-type channel blockers (8, 9, 30, 31), and others have suggested that hypoxia causes insufficient depolarization to activate L-type channels in the absence of some form of priming stimulus (24, 33, 38). In particular, Robertson et al. (30) showed that both the elevation in [Ca2+]i and HPV in small intrapulmonary arteries (IPA) were unaffected by simultaneous L-type channel blockade and depolarization with 80 mM K+ and suggested that hypoxia activates a voltage-independent Ca2+ entry pathway through unidentified nonselective cation channels (NSCC) (30).There is now a significant body of work suggesting that hypoxia-induced Ca2+ release from intracellular stores is an early and essential requirement for HPV (11, 16, 20, 32, 47). Store release activates store-operated channels (SOC) and capacitative Ca2+ entry (CCE) in many cell types (27), including PASM (18, 30, 34, 40, 48). Interestingly, CCE seems to have an unusually prominent role in distal IPA, since activation of CCE elicits vasoconstriction in distal IPA, but not in small systemic arteries (34). These factors all support the suggestion that CCE might contribute to the elevation in PASM [Ca2+]i during hypoxia (30, 43), and indeed in two recent papers hypoxia has been shown to activate CCE as a consequence of store release and thus elevate [Ca2+]i in freshly isolated (22) and cultured PASM cells (41). Nevertheless, changes in [Ca2+]i are not necessarily associated with vasoconstriction (e.g., Ref. 34), and these reports on their own cannot conclusively prove a physiological role for CCE in HPV.The decisive study by Weigand et al., the current article in focus (Ref. 45, see p. L5 in this issue), extends their previous work (41) to examine the role of CCE and NSCC in HPV of isolated perfused lungs of rats. The key findings of this study are that pharmacological agents (SKF-96365, Ni2+, and La3+) previously shown to block CCE in PASM cells were potent inhibitors of HPV at concentrations that did not affect L-type channels. This is the first direct evidence that CCE, or at least NSCC with a similar profile for block by these agents, plays a critical role in HPV. Intriguingly, blockade of either CCE or L-type channels virtually abolished the hypoxic pressor response in both cases (45). This contrasts with the hypoxia-induced elevation in [Ca2+]i in PASM cells, which was abolished by blockers of CCE but was only reduced by ∼50% by L-type channel blockers (22, 41). As discussed by Weigand et al. (45), it is conceivable that neither pathway alone is capable of raising [Ca2+]i sufficiently to support any vasoconstriction and that both are therefore required for HPV.It is also possible that the pathways are interdependent. For example, SOC underlying CCE are highly permeable to Na+ in PASM (21, 34), as for many other vascular smooth muscles. Activation would therefore tend to depolarize the cell, either sufficiently to activate L-type channels directly, or indirectly by providing the priming that has been reported necessary for hypoxia to cause inhibition of some types of K+ channel, and thus further depolarization (2, 33, 38). However, diltiazem did not affect thapsigargin-induced vasoconstriction in small IPA (34), and removal of extracellular Na+ did not affect HPV in the same preparation (3), arguing against any significant CCE-associated depolarization. Conversely, as argued by Robertson et al. (30), inhibition of L-type channels could alter the basal condition of the PASM cell, essentially removing an element of the priming that is known to potentiate or facilitate HPV and that may synergize with the pathways activated by hypoxia (reviewed in Refs. 13, 36, and 44). Certainly, in the presence of exogenous priming with prostaglandin F2α, both the elevation in [Ca2+]i and HPV in rat IPA were essentially unaffected by L-type channel blockers (30). Whatever the relationship between voltage-dependent and -independent Ca2+ entry during hypoxia, it is clear from the above, and particularly from the study of Weigand et al. (45), that CCE plays a central and probably preeminent role in HPV.Several questions remain to be answered. One is the molecular identity of the SOC activated during hypoxia. SOC and other NSCC are likely to be formed of homo- or heteromultimers of transient receptor potential (TRP) proteins (4, 5), and the majority of at least the canonical TRP channel family has been shown to be expressed in PASM (18, 21, 40). Several of these have been have been implicated in CCE from expression and knockdown studies in a variety of cell types, including PASM (e.g., Ref. 35), but the lack of specific pharmacological blockers severely hampers identification. It is almost certain that several types of SOC exist, possibly coupled to store emptying by different pathways (e.g., Ref. 26), and it seems likely that more than one may be present in any particular cell type. Whether these may be activated by emptying of different stores is unknown. This may be of relevance for disentangling the voltage-independent Ca2+ entry mechanisms that have been described during HPV.Hypoxia has been shown to cause release of a ryanodine-sensitive store in rat, rabbit, and canine PASM (10, 16, 47), although in canine PASM cells, simultaneous release from both ryanodine- and IP3-sensitive stores is required to activate CCE (48). CCE in the latter was not inhibited by 100 μM Gd3+, whereas the IC50 for La3+ on CCE in rat cultured PASM cells was ∼40 μM (40). In contrast, 1 μM La3+ or Gd3+ abolished both the CCE-associated vasoconstriction and Mn2+ quench in rat IPA and the associated inward current in PASM cells freshly isolated from IPA (34). Similarly, La3+ suppressed the transient first phase of HPV in rat IPA with an IC50 of ∼0.1 μM, although the IC50 for the sustained second phase was ∼50 μM (30). The latter is very similar to the value obtained from cultured PASM cells (40) and fits well with the degree of suppression of HPV elicited by 10 μM La3+ as reported by Weigand et al. (45) in perfused lungs. This differential sensitivity to lanthanides could be interpreted as reflecting the presence of more than one CCE pathway in PASM, possibly involving SOC with different activation mechanisms.There is also the possibility that hypoxia either activates an additional voltage-independent pathway that is independent of store emptying, but similar in terms of pharmacological block to CCE, or that it activates a mechanism such as Src or protein kinase C that potentiates CCE. This would be consistent with the finding of Wang et al. (41) that hypoxia could elicit a further increase in [Ca2+]i even after stores had been depleted with cyclopiazonic acid. Several NSCC and channels of the TRP superfamily have been reported to be directly activated by reactive oxygen species and/or modulated by protein kinases (reviewed in Ref. 43), including, rather intriguingly, a store-independent Ca2+ entry pathway that is regulated by Rho kinase (12, 15). Rho kinase is known to be involved in HPV, although it has been assumed that this is related purely to its role in Ca2+ sensitization, and both Src family kinases and protein kinase C have been implicated in the response (reviewed in Ref. 42). Thus the speculation that hypoxia may activate and/or potentiate voltage-independent Ca2+ entry, in addition to activation of CCE via store emptying, is perhaps worthy of further investigation.Another question relates to the mechanism by which hypoxia causes release of Ca2+ from intracellular stores. There is a fair degree of consensus that the O2 sensor resides in the mitochondrion, although the identity of the distal signaling pathways remains fraught with controversy (reviewed in Ref. 43). Nevertheless, there is strong evidence that cyclic ADP ribose-mediated Ca2+ release from ryanodine-sensitive stores is a critical event for HPV (10, 47). A key target for research is therefore a definitive demonstration of the mechanisms linking the mitochondrion to cyclic ADP ribose signaling.To summarize, the study of Weigand et al. (45) provides an important advance in the field, although it raises the question as to the relative importance of CCE and voltage-dependent Ca2+ entry during HPV. On the basis of currently available data, in particular the apparently critical dependence of HPV on Ca2+ release from stores (e.g., Refs. 16 and 47), it is tempting to speculate that CCE is the primary effector mechanism by which hypoxia elevates PASM [Ca2+]i, possibly relegating K+ channel inhibition and Ca2+ entry via L-type channels to a facilatory or permissive pathway. Only time will tell.GRANTSThe work referred to from our laboratory was supported by Wellcome Trust Grant 062554.AUTHOR NOTESAddress for reprint requests and other correspondence: Prof. J. P. T. Ward, Dept. of Asthma, Allergy, and Respiratory Medicine, 2nd Fl. 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