Activation of the basolateral membrane Cl- conductance essential for electrogenic K+ secretion suppresses electrogenic Cl- secretion.
Activation of the basolateral membrane Cl- conductance essential for electrogenic K+ secretion suppresses electrogenic Cl- secretion.
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DOI：
10.1113/expphysiol.2010.055038
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发表时间：
2011-03
影响因子：
2.7
通讯作者：
Halm DR
中科院分区：
文献类型：
--
作者：
He Q;Halm ST;Zhang J;Halm DR
肾上腺素激活豚鼠离体远端结肠粘膜的瞬时Cl−分泌和持续K+分泌。Ca++激活的Cl−通道抑制剂CaCCinh-A01 [30μM]显著降低了以短路电流（Isc）检测的生电性K+分泌。这种抑制作用支持了K+分泌的细胞模型，在该模型中，基底外侧膜Cl−通道为Cl−通过Na+/K+/2Cl−-共转运蛋白进入细胞提供了一条出口途径。CaCCinh-A01以浓度依赖性方式抑制Isc和跨上皮电导，IC 50 = 6.3μM。GlyH-101是另一种Cl−通道抑制剂，也可降低持续的肾上腺素激活的Isc（IC 50 = 9.4μM）。肾上腺素激活离体完整结肠隐窝中的全细胞Cl−电流，通过离子置换证实。这种肾上腺素激活的全细胞Cl−电流也被CaCCinh-A01或GlyH-101抑制。与K+分泌相反，CaCCinh-A01增强了肾上腺素激活的产电Cl−分泌以及PGE 2激活的产电Cl −分泌。由胆碱能/PGE 2刺激激活的协同Cl−分泌对CaCCinh-A01不敏感。通过RT-PCR检测Tmem 16 A-mRNA、使用Tmem 16 A抗体的免疫印迹和上皮细胞侧膜中的免疫荧光检测，支持了Ca++激活的Cl−通道蛋白Tmem 16 A的结肠表达。Tmem 16 A的选择性剪接被检测到参与通道激活的外显子。CaCCinh-A01对K+分泌的抑制和对Cl−分泌的增强支持了这两种离子分泌过程的常见结肠细胞模型，例如基底外侧膜Cl−通道的激活有助于产生电性K+分泌并限制Cl−分泌的速率。最大生理性Cl−分泌仅发生于关闭这些基底外侧膜Cl−通道的协同激活机制。
Adrenaline activates transient Cl−-secretion and sustained K+-secretion across isolated distal colonic mucosa of guinea pig. The Ca++-activated Cl− channel inhibitor CaCCinh-A01 [30μM] significantly reduced electrogenic K+-secretion, detected as short-circuit current (Isc). This inhibition supported the cell model for K+-secretion in which basolateral membrane Cl− channels provide an exit pathway for Cl− entering the cell via Na+/K+/2Cl−-cotransporters. CaCCinh-A01 inhibited both Isc and transepithelial conductance in a concentration dependent manner, IC50 = 6.3μM. GlyH-101, another Cl− channel inhibitor, also reduced sustained adrenaline-activated Isc (IC50 = 9.4μM). Adrenaline activated whole-cell Cl− current in isolated intact colonic crypts, confirmed by ion substitution. This adrenaline-activated whole-cell Cl− current also was inhibited by CaCCinh-A01 or GlyH-101. In contrast to K+-secretion, CaCCinh-A01 augmented the electrogenic Cl−-secretion activated by adrenaline as well as that activated by PGE2. Synergistic Cl−-secretion activated by cholinergic/PGE2 stimulation was insensitive to CaCCinh-A01. Colonic expression of the Ca++-activated Cl− channel protein Tmem16A was supported by RT-PCR detection of Tmem16A-mRNA, by immuno-blot with a Tmem16A-antibody, and by immuno-fluorescence detection in lateral membranes of epithelial cells. Alternative splices of Tmem16A were detected for exons that are involved in channel activation. Inhibition of K+-secretion and augmentation of Cl−-secretion by CaCCinh-A01 supports a common colonic cell model for these two ion secretory processes, such that activation of basolateral membrane Cl− channels contributes to the production of electrogenic K+-secretion and limits the rate of Cl−-secretion. Maximal physiological Cl−-secretion occurs only for synergistic activation mechanisms that close these basolateral membrane Cl− channels.
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DOI：
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发表时间：
2009-11-01
影响因子：
2.3
作者：
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2010-07-01
影响因子：
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