A novel role of intestine epithelial GABAergic signaling in regulating intestinal fluid secretion
A novel role of intestine epithelial GABAergic signaling in regulating intestinal fluid secretion
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DOI：
10.1152/ajpgi.00497.2011
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发表时间：
2012-08-01
影响因子：
4.5
通讯作者：
Li, Jingxin
中科院分区：
文献类型：
--
作者：
Li, Yan;Xiang, Yun-Yan;Li, Jingxin
Li Y，Xiang Y，Lu W，Liu C，Li J. A novel role of intestinal epithelial GABAergic signaling in regulating intestinal fluid secretion.美国生理学杂志胃肠和肝脏生理学303：G453-G460，2012年。首次发表于2012年6月14日; doi：10.1152/ajpgi.00497.2011。γ-氨基丁酸（GABA）是中枢神经系统中的主要抑制性神经递质，其通过谷氨酸脱羧酶（GAD）的酶活性产生。GABA通过阴离子通道A型受体（GABA（A）R）产生快速生物信号。有趣的是，在大鼠的空肠上皮中发现了GABA。本研究的目的是确定是否有功能的GABA信号系统存在于肠上皮细胞，如果是这样的GABA信号是否调节肠上皮细胞的功能。采用RT-PCR、Western blot和免疫组化等方法检测不同种属小肠上皮细胞中GABA信号蛋白的表达。采用穿孔膜片钳技术，研究了GABA对小肠上皮细胞IEC-18跨膜电流的影响。在用GABA（A）R激动剂和拮抗剂处理的小鼠中测量液体重量与肠长度的比率。用小鼠过敏性腹泻模型研究了GABA（A）R拮抗剂对过敏性腹泻的影响。在小鼠、大鼠、猪和人的小肠上皮细胞中鉴定了GABA、GAD和GABA（A）R亚基。GABA（A）R激动剂诱导内向电流和去极化IEC-18。GABA和GABA（A）R激动剂蝇蕈醇均能增加大鼠肠液分泌。GABA（A）R拮抗剂印防己毒素或gabazine可显著降低肠分泌增加，而河豚毒素则无此作用。用卵清蛋白（OVA）致敏和攻击的小鼠肠上皮中GABA信号蛋白的表达水平增加。经OVA处理的小鼠表现出腹泻，经口服给予加巴嗪或印防己毒素可减轻腹泻。哺乳动物肠上皮细胞存在一种内源性自分泌GABA能信号，可上调肠液分泌。肠GABA能信号在过敏性腹泻中增强，并且抑制该GABA信号系统可加重过敏性腹泻。
Li Y, Xiang Y, Lu W, Liu C, Li J. A novel role of intestine epithelial GABAergic signaling in regulating intestinal fluid secretion. Am J Physiol Gastrointest Liver Physiol 303: G453-G460, 2012. First published June 14, 2012; doi:10.1152/ajpgi.00497.2011.-gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system, and it is produced via the enzymatic activity of glutamic acid decarboxylase (GAD). GABA generates fast biological signaling through type A receptors (GABA(A)R), an anionic channel. Intriguingly, GABA is found in the jejunum epithelium of rats. The present study intended to determine whether a functional GABA signaling system exists in the intestinal epithelium and if so whether the GABA signaling regulates intestinal epithelial functions. RT-PCR, Western blot, and immunohistochemical assays of small intestinal tissues of various species were performed to determine the expression of GABA-signaling proteins in intestinal epithelial cells. Perforated patch-clamp recording was used to measure GABA-induced transmembrane current in the small intestine epithelial cell line IEC-18. The fluid weight-to-intestine length ratio was measured in mice that were treated with GABA(A)R agonist and antagonist. The effect of GABA(A)R antagonist on allergic diarrhea was examined using a mouse model. GABA, GAD, and GABA(A)R subunits were identified in small intestine epithelial cells of mice, rats, pigs, and humans. GABA(A)R agonist induced an inward current and depolarized IEC-18. Both GABA and the GABA(A)R agonist muscimol increased intestinal fluid secretion of rats. The increased intestinal secretion was largely decreased by the GABA(A)R antagonist picrotoxin or gabazine, but not by tetrodotoxin. The expression levels of GABA-signaling proteins were increased in the intestinal epithelium of mice that were sensitized and challenged with ovalbumin (OVA). The OVA-treated mice exhibited diarrhea, which was alleviated by oral administration of gabazine or picrotoxin. An endogenous autocrine GABAergic signaling exists in the mammalian intestinal epithelium, which up-regulates intestinal fluid secretion. The intestinal GABAergic signaling becomes intensified in allergic diarrhea, and inhibition of this GABA-signal system alleviates the allergic diarrhea.