Signaling mechanisms involved in the intestinal pro-secretory actions of hydrogen sulfide
Signaling mechanisms involved in the intestinal pro-secretory actions of hydrogen sulfide
复制标题
DOI：
10.1111/j.1365-2982.2010.01571.x
复制
发表时间：
2010-11-01
影响因子：
3.5
通讯作者：
Schemann, M.
中科院分区：
文献类型：
--
作者：
Krueger, D.;Foerster, M.;Schemann, M.
背景硫化氢在肠道中的作用涉及神经激活。本研究旨在通过使用TRPV1和其他信号通路的非选择性Trp阻断剂和抑制剂来揭示硫化氢促分泌效应的信号机制。方法采用小室电压钳技术，研究硫化氢供体NaHS对豚鼠和人结肠分泌的影响。选择性TRPV1阻断剂Capsazepine、AMG9801、SB705498、BCTC、LY294002(磷脂酰肌醇-3激酶(PI3K)抑制剂)、SKF96365(商店操作的钙通道阻滞剂)、2-APB(三磷酸肌醇阻断剂)和阿托品均能显著减少豚鼠和人组织NaHS诱发的分泌量，但不能被TRPA1阻断剂HC030031、L和T型钙通道拮抗剂所抑制。TRPV1拮抗剂的作用提示在多个部位存在非竞争性抑制。在豚鼠结肠中，Gd3+和La3+(非选择性Trp阻断剂)没有作用，而Ru红则减弱NaHS的作用；在人结肠中，Gd3+减弱NaHS的反应。在豚鼠，神经激肽-1和-3受体阻断剂和在人组织中，神经激肽-1和-2受体阻断剂都能抑制NAHS的反应。NaHS和辣椒素反应之间存在交叉脱敏。结论与推测硫化氢通过靶向表达TRPV1的传入神经引起粘膜分泌，而TRPV1通过释放P物质激活胆碱能分泌神经元，这种作用依赖于神经激肽-1、-2或-3受体。除TRPV1信号外，H_2S还可能作用于细胞内钙依赖通路和PI3K。
BackgroundH2S actions in the gut involve neural activation. This study aimed to reveal the signaling mechanisms responsible for the pro-secretory effect of H2S by using TRPV1 and unselective TRP blockers and inhibitors of other signaling cascades hitherto described to be targeted by H2S elsewhere.MethodsUssing chamber voltage clamp technique was used to study actions of the H2S donor NaHS on secretion in guinea-pig and human colon. NaHS effects on guinea-pig primary afferents were also evaluated.Key ResultsNaHS evoked secretion was significantly reduced in guinea-pig and human tissue by the selective TRPV1 blockers capsazepine, AMG9801, SB705498, BCTC; LY294002 (Phosphatidylinositol-3 kinase (PI3K) inhibitor), SKF96365 (store operated calcium channel blocker), 2-APB (inositol triphosphate blocker), and atropine but not by HC030031 (TRPA1 blocker) or L- and T-type calcium channel antagonists. Actions of TRPV1 antagonists suggested non-competitive inhibition at multiple sites. In guinea-pig colon, Gd3+and La3+ (unselective TRP blockers) had no effects while ruthenium red reduced NaHS effects; in human colon Gd3+attenuated NaHS response. NaHS response was inhibited by neurokinin-1 and -3 receptor blockers in guinea-pig and neurokinin-1 and -2 receptor blockade in human tissue. There was cross-desensitization between NaHS and capsaicin responses. NaHS induced capsazepine and LY294002 sensitive afferent discharge.Conclusions & InferencesH2S evokes mucosal secretion by targeting TRPV1 expressing afferent nerves which activate cholinergic secretomotor neurons via release of substance P acting in a species dependent manner on neurokinin-1, -2 or -3 receptors. Besides TRPV1 signaling H2S may target intracellular calcium dependent pathways and PI3K.