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首页> 外文期刊>American Journal of Physiology >Calcium signaling via two-pore channels: local or global, that is the question.
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Calcium signaling via two-pore channels: local or global, that is the question.

机译：钙通过两孔通道发出信号：局部或全局，这就是问题所在。

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摘要

Recently, we identified, for the first time, two-pore channels (TPCs, TPCN for gene name) as a novel family of nicotinic acid adenine dinucleotide phosphate (NAADP)-gated, endolysosome-targeted calcium release channels. Significantly, three subtypes of TPCs have been characterized, TPC1-3, with each being targeted to discrete acidic calcium stores, namely lysosomes (TPC2) and endosomes (TPC1 and TPC3). That TPCs act as NAADP-gated calcium release channels is clear, given that NAADP binds to high- and low-affinity sites associated with TPC2 and thereby induces calcium release and homologous desensitization, as observed in the case of endogenous NAADP receptors. Moreover, NAADP-evoked calcium signals via TPC2 are ablated by short hairpin RNA knockdown of TPC2 and by depletion of acidic calcium stores with bafilomycin. Importantly, however, NAADP-evoked calcium signals were biphasic in nature, with an initial phase of calcium release from lysosomes via TPC2, being subsequently amplified by calcium-induced calcium release (CICR) from the endoplasmic reticulum (ER). In marked contrast, calcium release via endosome-targeted TPC1 induced only spatially restricted calcium signals that were not amplified by CICR from the ER. These findings provide new insights into the mechanisms that cells may utilize to "filter" calcium signals via junctional complexes to determine whether a given signal remains local or is converted into a propagating global signal. Essentially, endosomes and lysosomes represent vesicular calcium stores, quite unlike the ER network, and TPCs do not themselves support CICR or, therefore, propagating regenerative calcium waves. Thus "quantal" vesicular calcium release via TPCs must subsequently recruit inositol 1,4,5-trisphoshpate receptors and/or ryanodine receptors on the ER by CICR to evoke a propagating calcium wave. This may call for a revision of current views on the mechanisms of intracellular calcium signaling. The purpose of this review is, therefore, to provide an appropriate framework for future studies in this area.
机译：最近，我们首次确定了双孔通道（TPC，TPCN为基因名称）作为烟酸腺嘌呤二核苷酸磷酸（NAADP）门控的，溶酶体靶向的钙释放通道的新家族。重要的是，已表征了TPC的三种亚型，即TPC1-3，每种亚型都针对离散的酸性钙库，即溶酶体（TPC2）和内体（TPC1和TPC3）。正如内源性NAADP受体所观察到的那样，考虑到NAADP结合与TPC2相关的高亲和力和低亲和力位点，从而诱导钙释放和同源脱敏，因此TPC充当NAADP门控钙释放通道。此外，通过TPC2的短发夹RNA敲低和通过巴氟霉素消耗酸性钙的能力消除了通过TPC2的NAADP引起的钙信号。然而，重要的是，NAADP引起的钙信号本质上是双相的，钙的初始阶段是通过TPC2从溶酶体释放的，随后是钙从内质网（ER）诱导的钙释放（CICR）放大的。与之形成鲜明对比的是，通过内体靶向的TPC1释放的钙仅诱导空间受限的钙信号，而该信号并未被CICR从ER放大。这些发现为细胞可用于通过结合复合物“过滤”钙信号以确定给定信号是保持局部信号还是转换为传播全局信号的​​机制提供了新见解。本质上，内体和溶酶体代表了囊状钙存储，与ER网络完全不同，TPC本身不支持CICR或传播再生的钙波。因此，经由TPC的“定量”囊泡钙释放必须随后通过CICR在ER上募集肌醇1,4,5-三磷酸酯受体和/或ryanodine受体，以引起钙的传播。这可能需要修订有关细胞内钙信号传导机制的当前观点。因此，本次审查的目的是为该领域的未来研究提供合适的框架。

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