NAADP on Target
NAADP on Target
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DOI：
10.1007/978-94-007-2888-2_14
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Patel, Sandip
中科院分区：
文献类型：
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作者：
Hooper, Robert;Patel, Sandip
烟酸腺嘌呤二核苷酸磷酸（NAADP）是一种有效的细胞内钙动员信使。许多证据表明NAADP靶向位于酸性细胞器上的新型Ca 2+通道，但这些通道的身份仍不清楚。最近的研究集中在一类新的离子通道，双孔通道（TPC）作为可能的分子靶点。这些通道的位置内溶酶体系统和他们的NAADP的敏感性匹配密切的哺乳动物细胞和海胆卵，其中NAADP的影响被发现的内源性NAADP敏感通道。此外，TPC与原型内质网（ER）Ca 2+通道的功能偶联也是匹配的。结合定点突变的生物物理分析表明，TPC是NAADP门控离子通道的成孔亚基。TPC具有独特的双重复结构，由N-连接的糖基化调节，并且在其N-末端具有内-溶酶体靶向基序。敲除研究表明，TPC调节平滑肌收缩，分化和内皮细胞活化与先前的研究表明NAADP在这些过程中。因此，多条证据表明，TPC可能是NAADP长期寻求的目标。
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent intracellular Ca2+-mobilising messenger. Much evidence indicates that NAADP targets novel Ca2+ channels located on acidic organelles but the identity of these channels has remained obscure. Recent studies have converged on a novel class of ion channels, the two-pore channels (TPCs) as likely molecular targets. The location of these channels to the endo-lysosomal system and their sensitivity to NAADP match closely those of endogenous NAADP-sensitive channels in both mammalian cells and sea urchin eggs, where the effects of NAADP were discovered. Moreover, the functional coupling of TPCs to archetypal endoplasmic reticulum (ER) Ca2+ channels is also matched. Biophysical analysis in conjunction with site-directed mutagenesis demonstrates that TPCs are pore-forming subunits of NAADP-gated ion channels. TPCs have a unique two-repeat structure, are regulated by N-linked glycosylation and harbor an endo-lysosomal targeting motif in their N-terminus. Knockdown studies have shown TPCs to regulate smooth muscle contraction, differentiation and endothelial cell activation consistent with previous studies implicating NAADP in these processes. Thus multiple lines of evidence indicate that TPCs are the likely long sought targets for NAADP.