The large-conductance Ca2+-activated K+ channel is essential for innate immunity.
The large-conductance Ca2+-activated K+ channel is essential for innate immunity.
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DOI：
10.1038/nature02356
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发表时间：
2004-02-26
期刊：
影响因子：
64.8
通讯作者：
Segal, AW
中科院分区：
文献类型：
--
作者：
Ahluwalia, J;Tinker, A;Clapp, LH;Duchen, MR;Abramov, AY;Pope, S;Nobles, M;Segal, AW
中性白细胞在先天免疫中具有关键作用。教条规定，致命的打击是通过活性氧（ROS）和卤素传递给微生物的，它们是NADPH氧化酶的产物，其损伤导致免疫缺陷。然而，最近的证据表明，微生物可能被蛋白酶杀死，通过在吞噬泡中产生高渗，富K+和碱性环境，由氧化酶激活。在这里，我们表明，K+穿过膜通过大电导钙激活的K+（BKCa）通道。这些通道的特异性抑制剂，iberiotoxin和paxilline，阻止氧化酶诱导的86 Rb+通量和碱化的吞噬空泡，而NS1619，BKCa通道开放剂，增强两者。在中性粒细胞和嗜酸性粒细胞中证实了特征性外向整流K+电流，可被伊比利亚毒素可逆抑制，并通过蛋白质印迹法证实了BK通道α亚基的表达。的通道被打开的膜去极化和升高的Ca2+浓度的组合，这两个后果的氧化酶活性。值得注意的是，当BKCa通道被阻断时，微生物杀灭和消化被取消，揭示了这种K+通道在杀微生物过程中的重要和意想不到的功能。
Neutrophil leukocytes have a pivotal function in innate immunity. Dogma dictates that the lethal blow is delivered to microbes by reactive oxygen species (ROS) and halogens, products of the NADPH oxidase, whose impairment causes immunodeficiency. However, recent evidence indicates that the microbes might be killed by proteases, activated by the oxidase through the generation of a hypertonic, K+-rich and alkaline environment in the phagocytic vacuole. Here we show that K+ crosses the membrane through large-conductance Ca2+-activated K+ (BKCa) channels. Specific inhibitors of these channels, iberiotoxin and paxilline, blocked oxidase-induced 86Rb+ fluxes and alkalinization of the phagocytic vacuole, whereas NS1619, a BKCa channel opener, enhanced both. Characteristic outwardly rectifying K+ currents, reversibly inhibited by iberiotoxin, were demonstrated in neutrophils and eosinophils and the expression of the α-subunit of the BK channel was confirmed by western blotting. The channels were opened by the combination of membrane depolarization and elevated Ca2+ concentration, both consequences of oxidase activity. Remarkably, microbial killing and digestion were abolished when the BKCa channel was blocked, revealing an essential and unexpected function for this K+ channel in the microbicidal process.
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