Abolition of Ca2+-mediated intestinal anion secretion and increased stool dehydration in mice lacking the intermediate conductance Ca2+-dependent K+ channel Kcnn4
Abolition of Ca2+-mediated intestinal anion secretion and increased stool dehydration in mice lacking the intermediate conductance Ca2+-dependent K+ channel Kcnn4
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DOI：
10.1113/jphysiol.2007.134387
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发表时间：
2007-09-01
影响因子：
5.5
通讯作者：
Sepulveda, Francisco V.
中科院分区：
文献类型：
--
作者：
Flores, Carlos A.;Melvin, James E.;Sepulveda, Francisco V.
肠液分泌由顶端膜、囊性纤维化跨膜传导调节因子（CFTR）介导的Cl-外排驱动，Cl-通过基底外侧Na+-K+-2Cl（-）共转运蛋白（NKCC 1）在细胞中浓缩。Cl-流出的一个绝对要求是平行激活维持膜电位的通道，维持顶端阴离子分泌。cAMP和Ca ~（2+）都是肠道分泌Cl ~-的细胞内信号。参与cAMP依赖性分泌的K+通道已被鉴定为KCNQ 1-KCNE 3复合物，但驱动Ca 2+激活的Cl-分泌的K+通道的身份存在争议。我们现在已经使用了Kcnn 4空小鼠，以表明中间电导IK 1 K+通道是必要的，足以支持Ca 2+依赖的Cl-分泌在大肠和小肠。使用Ussing室监测对照小鼠和Kcnn 4缺失小鼠结肠和空肠中的跨上皮电位、电阻和等效短路电流。同时测定粪便中Na+、K+和含水量。Kcnn 4基因敲除小鼠的远端结肠和小肠上皮细胞具有正常的cAMP依赖性Cl-分泌反应。相反，他们完全缺乏Cl-分泌响应Ca 2+动员激动剂。在IK 1通道缺陷的小鼠结肠上皮中，Ca 2+激活的产电性K+分泌增加。在IK 1无效动物中，粪便的Na+和水含量减少。使用Kcnn 4 nun小鼠使我们能够证明伊基K+通道仅负责驱动肠Ca 2+激活的Cl-分泌。该通道的缺失导致粪便中的含水量显著减少，可能是由于电解质和水分泌减少。
Intestinal fluid secretion is driven by apical membrane, cystic fibrosis transmembrane conductance regulator (CFTR)-mediated efflux of Cl- that is concentrated in cells by basolateral Na+-K+-2Cl(-) cotransporters (NKCC1). An absolute requirement for Cl- efflux is the parallel activation of channels which maintain a membrane potential that sustains apical anion secretion. Both cAMP and Ca2+ are intracellular signals for intestinal Cl- secretion. The K+ channel involved in cAMP-dependent secretion has been identified as the KCNQ1-KCNE3 complex, but the identity of the K+ channel driving Ca2+-activated Cl- secretion is controversial. We have now used a Kcnn4 null mouse to show that the intermediate conductance IK1 K+ channel is necessary and sufficient to support Ca2+-dependent Cl- secretion in large and small intestine. Ussing chambers were used to monitor transepithelial potential, resistance and equivalent short-circuit current in colon and jejunum from control and Kcnn4 null mice. Na+, K+ and water content of stools was also measured. Distal colon and small intestinal epithelia from Kcnn4 null mice had normal cAMP-dependent Cl- secretory responses. In contrast, they completely lacked Cl- secretion in response to Ca2+ -mobilizing agonists. Ca2+-activated electrogenic K+ secretion was increased in colon epithelium of mice deficient in the IK1 channel. Na+ and water content of stools was diminished in IK1-null animals. The use of Kcnn4 nun mice has allowed us to demonstrate that IKI K+ channels are solely responsible for driving intestinal Ca2+ -activated Cl- secretion. The absence of this channel leads to a marked reduction in water content in the stools, probably as a consequence of decreased electrolyte and water secretion.