Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing second messenger whose formation has remained elusive. In vitro, CD38‐mediated NAADP synthesis requires an acidic pH and a nonphysiological concentration of nicotinic acid (NA). We discovered that CD38 catalyzes synthesis of NAADP by exchanging the nicotinamide moiety of nicotinamide adenine dinucleotide phosphate (NADP+) for the NA group of nicotinic acid adenine dinucleotide (NAAD) inside endolysosomes of interleukin 8 (IL8)‐treated lymphokine‐activated killer (LAK) cells. Upon IL8 stimulation, cytosolic NADP+ is transported to acidified endolysosomes via connexin 43 (Cx43) and gated by cAMP‐EPAC‐RAP1‐PP2A signaling. CD38 then performs a base‐exchange reaction with the donor NA group deriving from NAAD, produced by newly described endolysosomal activities of NA phosphoribosyltransferase (NAPRT) and NMN adenyltransferase (NMNAT) 3. Thus, the membrane organization of endolysosomal CD38, a signal‐mediated transport system for NADP+ and luminal NAD+ biosynthetic enzymes integrate signals from a chemokine and cAMP to specify the spatiotemporal mobilization of Ca2+ to drive cell migration.

中文翻译：

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Interleukin‐8 在内溶酶体中驱动 CD38 从 NADP + 和 NAAD 形成 NAADP，从而动员 Ca 2+ 并影响细胞迁移

烟酸腺嘌呤二核苷酸磷酸 (NAADP) 是最有效的 Ca2+ 动员第二信使，其形成仍难以捉摸。在体外，CD38 介导的 NAADP 合成需要酸性 pH 值和非生理浓度的烟酸 (NA)。我们发现，CD38 通过将烟酰胺腺嘌呤二核苷酸磷酸 (NADP+) 的烟酰胺部分交换为白细胞介素 8 (IL8) 处理的淋巴因子激活杀伤细胞 (LAK) 的内溶酶体内烟酸腺嘌呤二核苷酸 (NAAD) 的 NA 基团来催化 NAADP 的合成细胞。IL8 刺激后，胞质 NADP+ 通过连接蛋白 43 (Cx43) 转运至酸化的内溶酶体，并由 cAMP-EPAC-RAP1-PP2A 信号传导进行门控。然后，CD38 与源自 NAAD 的供体 NA 基团进行碱基交换反应，NAAD 是由新描述的 NA 磷酸核糖基转移酶 (NAPRT) 和 NMN 腺苷酸转移酶 (NMNAT) 3 的内溶酶体活性产生的。因此，内溶酶体 CD38 的膜组织是信号介导的NADP+ 和管腔 NAD+ 生物合成酶的转运系统整合来自趋化因子和 cAMP 的信号，以指定 Ca2+ 的时空动员，以驱动细胞迁移。