Cyclic AMP-induced K+ secretion occurs independently of Cl- secretion in rat distal colon.
Cyclic AMP-induced K+ secretion occurs independently of Cl- secretion in rat distal colon.
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DOI：
10.1152/ajpcell.00099.2012
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发表时间：
2012-08
期刊：
影响因子：
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通讯作者：
G. Sandle;V. Rajendran
中科院分区：
文献类型：
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作者：
G. Sandle;V. Rajendran
cAMP在哺乳动物结肠中诱导活性Cl（-）和活性K（+）分泌。一般认为，K（+）退出的机制是维持细胞处于超极化状态所必需的，因此有利于持续的Cl（-）分泌。Kcnn 4c和Kcnma 1通道均位于结肠，本研究探讨了Kcnn 4c和/或Kcnma 1通道是否介导cAMP诱导的K（+）分泌以及cAMP诱导的K（+）分泌是否为Cl（-）分泌提供驱动力。在电压钳条件下同时测量了结肠粘膜中毛喉素（FSK）增强的短路电流（净生电离子转运的指标）和K（+）通量。粘蛋白Na（+）orthovanadate（P-型ATP酶抑制剂）抑制大鼠远端结肠正常存在的活性K（+）吸收。在粘膜原钒酸钠存在下，serovine FSK诱导K（+）和Cl（-）分泌。FSK诱导的K（+）分泌1）不受粘膜或血清1-[（2-氯苯基）二苯甲基]-1H-吡唑（TRAM-34;一种Kcnn 4通道阻滞剂）的抑制，2）受粘膜伊比利亚毒素（Kcnma 1通道阻滞剂）的抑制（92%），3）不受粘膜囊性纤维化跨膜传导调节因子抑制剂（CFTR（inh）-172）的影响。相比之下，FSK诱导的Cl（-）分泌1）完全被丝氨酸蛋白酶TRAM-34抑制，2）不被粘膜或丝氨酸蛋白酶伊比利亚毒素抑制，3）完全被粘膜CFTR（inh）-172抑制。这些结果表明，cAMP诱导的结肠K（+）分泌是通过位于顶膜的Kcnma 1通道介导的，并且很可能导致分泌性腹泻中粪便K（+）的损失。另一方面，cAMP诱导的结肠Cl（-）分泌需要位于基底外侧膜的Kcnn 4 b通道的活性，而不依赖于顶端Kcnma 1通道的同时激活。
cAMP induces both active Cl(-) and active K(+) secretion in mammalian colon. It is generally assumed that a mechanism for K(+) exit is essential to maintain cells in the hyperpolarized state, thus favoring a sustained Cl(-) secretion. Both Kcnn4c and Kcnma1 channels are located in colon, and this study addressed the questions of whether Kcnn4c and/or Kcnma1 channels mediate cAMP-induced K(+) secretion and whether cAMP-induced K(+) secretion provides the driving force for Cl(-) secretion. Forskolin (FSK)-enhanced short-circuit current (indicator of net electrogenic ion transport) and K(+) fluxes were measured simultaneously in colonic mucosa under voltage-clamp conditions. Mucosal Na(+) orthovanadate (P-type ATPase inhibitor) inhibited active K(+) absorption normally present in rat distal colon. In the presence of mucosal Na(+) orthovanadate, serosal FSK induced both K(+) and Cl(-) secretion. FSK-induced K(+) secretion was 1) not inhibited by either mucosal or serosal 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34; a Kcnn4 channel blocker), 2) inhibited (92%) by mucosal iberiotoxin (Kcnma1 channel blocker), and 3) not affected by mucosal cystic fibrosis transmembrane conductance regulator inhibitor (CFTR(inh)-172). By contrast, FSK-induced Cl(-) secretion was 1) completely inhibited by serosal TRAM-34, 2) not inhibited by either mucosal or serosal iberiotoxin, and 3) completely inhibited by mucosal CFTR(inh)-172. These results indicate that cAMP-induced colonic K(+) secretion is mediated via Kcnma1 channels located in the apical membrane and most likely contributes to stool K(+) losses in secretory diarrhea. On the other hand, cAMP-induced colonic Cl(-) secretion requires the activity of Kcnn4b channels located in the basolateral membrane and is not dependent on the concurrent activation of apical Kcnma1 channels.