Ma Ruolin, Seifi Mohsen, Papanikolaou Maria, Brown James F, Swinny Jerome D, Lewis Anthony
School of Pharmacy and Biomedical Sciences, Institute of Biological and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
Front Physiol. 2018 Mar 6;9:157. doi: 10.3389/fphys.2018.00157. eCollection 2018.
Gastrointestinal (GI) motility disorders such as irritable bowel syndrome (IBS) can occur when coordinated smooth muscle contractility is disrupted. Potassium (K) channels regulate GI smooth muscle tone and are key to GI tract relaxation, but their molecular and functional phenotypes are poorly described. Here we define the expression and functional roles of mechano-gated K channels in mouse ileum and colon. Expression and distribution of the K channel family were investigated using quantitative RT-PCR (qPCR), immunohistochemistry and confocal microscopy. The contribution of mechano-gated K channels to mouse intestinal muscle tension was studied pharmacologically using organ bath. Multiple K gene transcripts were detected in mouse ileum and colon whole tissue preparations. Immunohistochemistry confirmed TREK-1 expression was smooth muscle specific in both ileum and colon, whereas TREK-2 and TRAAK channels were detected in enteric neurons but not smooth muscle. In organ bath, mechano-gated K channel activators (Riluzole, BL-1249, flufenamic acid, and cinnamyl 1-3,4-dihydroxy-alpha-cyanocinnamate) induced relaxation of KCl and CCh pre-contracted ileum and colon tissues and reduced the amplitude of spontaneous contractions. These data reveal the specific expression of mechano-gated K channels in mouse ileum and colon tissues and highlight TREK-1, a smooth muscle specific K channel in GI tract, as a potential therapeutic target for combating motility pathologies arising from hyper-contractility.
当协调性平滑肌收缩性受到破坏时，可能会发生诸如肠易激综合征（IBS）等胃肠（GI）动力障碍。钾（K）通道调节胃肠平滑肌张力，是胃肠道松弛的关键，但它们的分子和功能表型描述甚少。在这里，我们定义了机械门控钾通道在小鼠回肠和结肠中的表达及功能作用。使用定量逆转录聚合酶链反应（qPCR）、免疫组织化学和共聚焦显微镜研究了钾通道家族的表达和分布。使用器官浴槽，通过药理学方法研究了机械门控钾通道对小鼠肠肌张力的作用。在小鼠回肠和结肠全组织标本中检测到多个钾基因转录本。免疫组织化学证实，TREK-1在回肠和结肠中的表达均具有平滑肌特异性，而TREK-2和TRAAK通道在肠神经元中检测到，但在平滑肌中未检测到。在器官浴槽中，机械门控钾通道激活剂（利鲁唑、BL-1249、氟芬那酸和肉桂基1-3,4-二羟基-α-氰基肉桂酸酯）可诱导氯化钾和氯化乙酰胆碱预收缩的回肠和结肠组织松弛，并降低自发收缩的幅度。这些数据揭示了机械门控钾通道在小鼠回肠和结肠组织中的特异性表达，并突出了TREK-1，一种胃肠道平滑肌特异性钾通道，作为对抗因过度收缩引起的动力障碍的潜在治疗靶点。
