Non-voltage-gated Ca²⁺ entry pathways in the heart: the untold STOrai?
Non-voltage-gated Ca²⁺ entry pathways in the heart: the untold STOrai?
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心脏中的非电压门控 Ca2+ 进入途径：不为人知的 STOrai？
DOI：
10.1093/cvr/cvu217
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发表时间：
2015
影响因子：
10.8
通讯作者：
Chatham,JohnC
中科院分区：
文献类型：
--
作者：
Collins,HelenE;Chatham,JohnC
我们对心肌细胞Ca~(2+)处理的理解主要基于电压门控的Ca~(2+)通过L型钙通道(LTCC)进入肌浆网(SR)，以及由此产生的Ca~(2+)诱导肌浆网(SR)的钙释放。钙离子被广泛认为在所有细胞中起着关键的信号作用，而在心肌细胞中，最普遍接受的途径是通过内质网(ER)/SR和核膜等细胞内存储释放钙离子。然而，在不可兴奋的细胞中，激动剂介导的细胞内钙离子增加是由于钙离子跨膜进入而发生的。这些途径中研究最广泛的是Putney 1所描述的存储操作的钙离子进入(SOCE)，其中三磷酸肌醇(IP3)诱导的内质网/SR库中的钙离子释放触发了随后的细胞外钙内流，这是随后激活下游信号通路所必需的，也是重新填充ER/SR所必需的。这些钙信号已被证明在包括新陈代谢、转录和分化在内的各种细胞反应的调节中发挥关键作用。最早证明SOCE对心肌细胞中的钙信号有贡献的报告之一是在2002年，Marchase和他的同事2发现，苯肾上腺素或血管紧张素激活激活的T细胞的核因子(NFAT)，从而导致的心肌细胞肥大是SOCE依赖的。当时，负责调节SOCE的蛋白质还不清楚；但在2005年，随着基质相互作用分子(STIM)和Orai蛋白家族的鉴定，SOCE的分子调节因子终于被阐明。现在普遍认为，ER/SR膜蛋白STIM1与质膜蛋白Orai1的偶联是促进SOCE的主要机制。虽然最近对非电压门控钙信号和心肌肥大的研究主要集中在STIM和Orai介导的途径上，但应该注意的是，也涉及瞬时受体电位通道；然而，有人认为这可能涉及钙通过LTCC进入。3显然，要了解非电压门控和电压门控的钙信号在心脏中的相对重要性，还需要进一步的研究。除了SOCE，还有越来越多的证据表明，另一种非电压门控的钙进入途径--存储非依赖性钙进入(SICE)，主要特征是内源性花生四烯酸调节的钙通道(ARC)，它具有类似于SOCE的电流/电压特性，但不需要存储耗尽。有趣的是，ARC通道的激活被报道涉及Orai1和Orai3 4-6的异构体组装以及与质膜定位的STIM1的偶联。7值得注意的是，虽然STIM和Orai蛋白家族高度保守，无脊椎动物只有一种Orai蛋白，而脊椎动物有两种Orai蛋白，但Orai3似乎是哺乳动物细胞所特有的。6虽然已经有许多研究支持STIM1和SOCE在介导心肌细胞肥大中的作用，但对心脏中SICE或ARC的活动知之甚少。因此，Saliba等人的这项研究，重点是STIM1与Orai1和Orai3的相互作用以及它们在心肌细胞钙内流中的作用，是非常新颖和及时的。他们首次证实Orai3和ARC通道参与了大鼠心肌细胞的非电压门控钙离子进入和肥大信号传递。他们发现Orai1、Orai3和Stim1是…
Our understanding of cardiomyocyte Ca2+ handling is primarily based on the regulation of voltage-gated Ca2+ entry, via L-type Ca2+ channels (LTCCs), and the resulting Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR) required for excitation–contraction coupling. Ca2+ is widely recognized as playing a key signalling role in all cells, and in cardiomyocytes the most commonly accepted pathway involves Ca2+ release from intracellular stores such as the endoplasmic reticulum (ER)/SR and the nuclear envelope. However, in non-excitable cells, agonist-mediated increases in intracellular Ca2+ are known to occur as a result of Ca2+ entry across the plasma membrane. The most widely studied of these pathways is store-operated Ca2+ entry (SOCE) as described by Putney 1 where Inositol 1, 4, 5 Triphosphate (IP3)-induced release of Ca2+ from ER/SR stores triggered a subsequent influx of extracellular Ca2+, which was required both for subsequent activation of downstream signalling pathways and also for refilling of ER/SR. Such Ca2+ signals have been shown to play a key role in the regulation of diverse cellular responses, including metabolism, transcription, and differentiation. One of the earliest reports demonstrating that SOCE contributed to Ca2+ signalling in cardiomyocytes was in 2002 where Marchase and colleagues 2 showed that activation of nuclear factor of activated T-cells (NFAT) by phenylephrine or angiotensin and the resulting cardiomyocyte hypertrophy was SOCE-dependent. At that time the proteins responsible for regulating SOCE were unknown; however, in 2005 with the identification of stromal interaction molecule (STIM) and Orai protein families, the molecular mediators of SOCE were finally elucidated. It is now generally accepted that the coupling of the ER/SR membrane protein STIM1 with the plasma membrane protein Orai1 is a major mechanism facilitating SOCE. While the most recent studies on non-voltage-gated Ca2+ signalling and cardiomyocyte hypertrophy have focused on STIM and Orai-mediated pathways, it should be noted that transient receptor potential channels have also been implicated; however, it has been suggested that this may involve Ca2+ entry via LTCC. 3 Clearly, further studies are needed to understand the relative importance of non-voltage-gated and voltage-gated Ca2+ signalling in the heart.In addition to SOCE, there is also growing evidence of another nonvoltage-gated Ca2+ entry pathway, store-independent Ca2+ entry (SICE), primarily characterized as an endogenous arachidonic acid-regulated Ca2+(ARC) channel, which has current/voltage characteristics similar to SOCE, but does not require store depletion. Interestingly, ARC channel activation has been reported to involve a heteromeric assembly of Orai1 and Orai3 4–6 as well as coupling with plasma membrane localized STIM1. 7 It is of note that while STIM and Orai protein families are highly conserved, with invertebrates having only a single Orai protein and vertebrates two Orai proteins, Orai3 appears to be specific for mammalian cells. 6 While there have been a number of studies supporting a role of STIM1 and SOCE in mediating cardiomyocyte hypertrophy, little is known about SICE or ARC activity in the heart. Consequently, the study by Saliba et al., 8 which focuses on the interaction between STIM1 with Orai1 and Orai3 and their role in Ca2+ influx in cardiomyocytes, is both highly novel and timely. They demonstrated for the first time the involvement of Orai3 and ARC channels in non-voltage-gated Ca2+ entry and hypertrophic signalling in rat cardiomyocytes. They found that Orai1, Orai3 and STIM1 were …