Both sides now: multiple interactions of ATP with pannexin-1 hemichannels. Focus on "A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP"
Both sides now: multiple interactions of ATP with pannexin-1 hemichannels. Focus on "A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP"
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DOI：
10.1152/ajpcell.00639.2008
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发表时间：
2009-02-01
影响因子：
5.5
通讯作者：
Dubyak, George R.
中科院分区：
文献类型：
--
作者：
Dubyak, George R.
ATP和其他核苷酸如何从完整细胞中释放是一个基本问题，因为在大多数脊椎动物组织中存在多个嘌呤能受体信号级联反应（25）。已经确定神经元和神经内分泌细胞通过经典机制释放ATP，所述经典机制涉及与专门分泌囊泡或颗粒内的其他神经递质共包装的核苷酸的Ca 2依赖性胞吐释放。然而，许多，实际上是大多数，非兴奋性细胞类型局部释放ATP通过非裂解机制，不涉及明显的或容易测量的含核苷酸的囊泡或颗粒的胞吐。非溶解性ATP释放的另一种机制是其通过质膜转运蛋白从胞质隔室的易化流出。各种膜转运蛋白或功能特征性渗透途径已被认为是"ATP通道"，包括一些ATP结合盒（ABC）家族转运蛋白、体积调节阴离子通道、线粒体电压依赖性阴离子通道（VDAC）孔蛋白的质膜变体和最大阴离子通道（31）。此外，越来越多的数据表明，许多细胞类型的ATP释放是由所谓的半通道介导的，半通道由来自已充分表征的连接蛋白（Cx）家族或最近描述的泛连接蛋白（Panx）家族的蛋白亚基组成（19，23，26）。半通道可以作为ATP和其他胞质代谢物流出的低阻力管道（59）。Panx1基因在大多数组织和细胞类型中的普遍表达表明，Panx1半通道可能是最广泛使用的外排途径之一，用于在不同的旁分泌和自分泌信号应答中释放ATP（4，30）。值得注意的是，细胞外ATP本身通过某些P2Y或P2X受体起作用，可以引发有利于半通道门控到开放状态的细胞内信号。这促进了与旁分泌信号传导"波"相关的可称为"ATP诱导的ATP释放"的途径，所述旁分泌信号传导"波"允许组织内的多个细胞主动响应环境应激（例如，代谢抑制、机械剪切和微生物侵入），所述环境应激仅由环境损伤或刺激的直接位点处的少数细胞感知（51）。这种旁分泌信号可以在适应性反应中发挥积极作用，例如缺血预处理，缓解机械应力或杀死入侵的病原体，对整个动物具有明显的生理益处。然而，与ATP可渗透半通道的门控偶联的P2受体激活级联也包括正反馈回路，如果不受限制，则可能导致细胞内ATP储存的适应不良和恶性消耗、离子梯度的崩溃和细胞死亡。因此，相当多的注意力已经指向鉴定可以抑制或限制半通道的门控/传导的内源性因子。在Qui和Dahl（40a）的论文中，他们描述了基于细胞外ATP对泛连接蛋白-1半通道的门控和/或活性的直接抑制作用的高度新颖的机制。
HOW ATP AND OTHER NUCLEOTIDES are released from intact cells is a fundamental question, given the existence of multiple purinergic receptor signaling cascades operative in most vertebrate tissues (25). It is well-established that neurons and neuroendocrine cells release ATP via classical mechanisms involving Ca2-dependent exocytotic release of nucleotides copackaged with other neurotransmitters within specialized secretory vesicles or granules. However, many, indeed most, nonexcitable cell types locally release ATP via nonlytic mechanisms that do not involve obvious or readily measured exocytosis of nucleotide-containing vesicles or granules. An alternative mechanism for nonlytic ATP release is its facilitated efflux from the cytosolic compartment through plasma membrane transport proteins. Various membrane transport proteins or functionally characterized permeability pathways have been suggested as “ATP channels,” including some ATP-binding cassette (ABC)-family transporters, volume-regulated anion channels, plasma membrane variants of the mitochondrial voltage-dependent anion channel (VDAC) porins, and maxianion channels (31). Additionally, a strong and growing body of data indicates that ATP release from many cell types is mediated by so-called hemichannels composed of protein subunits from the wellcharacterized connexin (Cx) family or the recently described pannexin (Panx) family (19, 23, 26). Hemichannels can act as low-resistance conduits for the efflux of ATP and other cytosolic metabolites (59). The ubiquitous expression of the Panx1 gene in most tissues and cell types suggests that Panx1 hemichannels may comprise one of the most widely used efflux pathways for ATP release in different paracrine and autocrine signaling responses (4, 30). Notably, extracellular ATP itself, acting via certain P2Y or P2X receptors, can elicit intracellular signals that favor the gating of hemichannels to the open state. This facilitates a pathway of what can be termed “ATP-induced ATP release” linked to paracrine signaling “waves” that allow multiple cells within a tissue to respond proactively to environmental stresses (eg, metabolic inhibition, mechanical shear, and microbial invasion) sensed by only a few cells at the immediate locus of environmental insult or stimulation (51). This sort of paracrine signaling can play a positive role in adaptive responses, such as ischemic preconditioning, relief of mechanical stress, or killing of invading pathogens, with clear physiological benefit to the whole animal. However, a cascade of P2 receptor activation coupled to the gating of ATP-permeable hemichannels also comprises a positive feedback loop that, if unrestrained, could lead to maladaptive and malignant depletion of intracellular ATP stores, collapse of ionic gradients, and cell death. Thus considerable attention has been directed toward the identification of endogenous factors that can inhibit or restrict the gating/conductance of hemichannels. In a paper by Qui and Dahl (40a), they describe a highly novel mechanism based on a direct inhibitory action of extracellular ATP on the gating and/or activity of pannexin-1 hemichannels.