Of the established Ca2+-mobilizing messengers, NAADP is arguably the most tantalizing. It is the most potent, often efficacious at low nanomolar concentrations, and its receptors undergo dramatic desensitization. Recent studies have identified a new class of calcium-release channel, the two-pore channels (TPCs), as the likely targets for NAADP regulation, even though the effect may be indirect. These channels localized at endolysosomes, where they mediate local Ca2+ release, and have highlighted a new role of acidic organelles as targets for messenger-evoked Ca2+ mobilization. Three distinct roles of TPCs have been identified. The first is to effect local Ca2+ release that may play a role in endolysosomal function including vesicular fusion and trafficking. The second is to trigger global calcium release by recruiting Ca2+-induced Ca2+-release (CICR) channels at lysosomal-endoplasmic reticulum (ER) junctions. The third is to regulate plasma membrane excitability by the targeting of Ca2+ release from appropriately positioned subplasma membrane stores to regulate plasma membrane Ca2+-activated channels. In this review, I discuss the role of nicotinic acid adenine nucleotide diphosphate (NAADP)-mediated Ca2+ release from endolysosomal stores as a widespread trigger for intracellular calcium signaling mechanisms, and how studies of TPCs are beginning to enhance our understanding of the central role of lysosomes in Ca2+ signaling.

中文翻译：

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NAADP受体。

在已建立的动员Ca2 +的使者中，NAADP无疑是最诱人的。它在低纳摩尔浓度下是最有效的，通常是有效的，并且其受体会发生明显的脱敏作用。最近的研究已经确定了一种新型的钙释放通道，即两孔通道（TPC），它可能是NAADP调节的靶标，即使这种作用可能是间接的。这些通道位于溶酶体中，它们在其中介导局部Ca2 +释放，并突出了酸性细胞器作为信使诱发的Ca2 +动员的新作用。已经确定了TPC的三个不同角色。首先是影响Ca2 +的局部释放，该释放可能在溶酶体功能（包括水泡融合和运输）中起作用。第二个是通过在溶酶体-内质网（ER）连接处募集Ca2 +诱导的Ca2 +释放（CICR）通道来触发全局钙释放。第三是通过靶向从适当定位的亚质膜存储中释放的Ca2 +来调节质膜的兴奋性，从而调节质膜Ca2 +激活的通道。在这篇综述中，我讨论了烟酸腺嘌呤核苷酸二磷酸（NAADP）介导的从溶酶体储存中释放的Ca2 +作为细胞内钙信号传导机制的广泛触发因素的作用，以及TPC的研究如何开始增强我们对HPC核心作用的理解。 Ca2 +信号传导中的溶酶体。第三是通过靶向从适当定位的亚质膜存储中释放的Ca2 +来调节质膜的兴奋性，从而调节质膜Ca2 +激活的通道。在这篇综述中，我讨论了烟酸腺嘌呤核苷酸二磷酸（NAADP）介导的从溶酶体储存中释放的Ca2 +作为细胞内钙信号传导机制的广泛触发因素的作用，以及TPC的研究如何开始增强我们对HPC核心作用的理解。 Ca2 +信号传导中的溶酶体。第三是通过靶向从适当定位的亚质膜存储中释放的Ca2 +来调节质膜的兴奋性，从而调节质膜Ca2 +激活的通道。在这篇综述中，我讨论了烟酸腺嘌呤核苷酸二磷酸（NAADP）介导的从溶酶体储存中释放的Ca2 +作为细胞内钙信号传导机制的广泛触发因素的作用，以及TPC的研究如何开始增强我们对HPC核心作用的理解。 Ca2 +信号传导中的溶酶体。