Peripheral K(V)7 channels regulate visceral sensory function in mouse and human colon.
Peripheral K(V)7 channels regulate visceral sensory function in mouse and human colon.
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DOI：
10.1177/1744806917709371
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发表时间：
2017-01
期刊：
影响因子：
3.3
通讯作者：
Blackshaw LA
中科院分区：
文献类型：
--
作者：
Peiris M;Hockley JR;Reed DE;Smith ESJ;Bulmer DC;Blackshaw LA
慢性内脏痛是许多胃肠道疾病的典型症状。电压门控钾通道的KV 7家族（KV7.1-KV7.5）介导调节外周感觉伤害感受器和中枢疼痛通路中的兴奋性的M电流。在这里，我们使用免疫组织化学，肠神经电生理记录在小鼠和人体组织，和单细胞定性实时聚合酶链反应的肠投射感觉神经元相结合，调查外周KV 7通道内脏伤害性感受的贡献。小鼠结肠的免疫组织化学染色显示，在肌间神经丛的内在肠神经元周围和沿着肠系膜血管的外在感觉纤维内，用CGRP标记KV 7亚型（KV 7.3和KV 7.5）。用KV 7开放剂瑞替加滨治疗几乎完全消除了由促藻原缓激肽诱发的内脏传入放电，与单细胞定性实时聚合酶链反应KCNQ亚型和B2缓激肽受体在结肠逆行标记的外源性感觉神经元中的mRNA转录物的显著共表达一致。瑞替加滨还以浓度依赖性方式减弱了对有害性扩张（0-80 mmHg）后肠机械刺激的反应，而KV 7阻断剂XE 991增强了这种反应。在人肠组织中，KV 7.3和KV 7.5在与突触素和CGRP共标记的神经元静脉曲张中表达，瑞替加滨抑制缓激肽诱导的人结肠传入记录中的传入激活。我们发现，KV 7通道有助于内脏感觉神经元的敏感性有害的化学和机械刺激在小鼠和人类肠道组织。因此，外周限制性KV 7开放剂可以代表用于治疗胃肠道病变的可行的治疗方式。
Chronic visceral pain is a defining symptom of many gastrointestinal disorders. The KV7 family (KV7.1–KV7.5) of voltage-gated potassium channels mediates the M current that regulates excitability in peripheral sensory nociceptors and central pain pathways. Here, we use a combination of immunohistochemistry, gut-nerve electrophysiological recordings in both mouse and human tissues, and single-cell qualitative real-time polymerase chain reaction of gut-projecting sensory neurons, to investigate the contribution of peripheral KV7 channels to visceral nociception. Immunohistochemical staining of mouse colon revealed labelling of KV7 subtypes (KV7.3 and KV7.5) with CGRP around intrinsic enteric neurons of the myenteric plexuses and within extrinsic sensory fibres along mesenteric blood vessels. Treatment with the KV7 opener retigabine almost completely abolished visceral afferent firing evoked by the algogen bradykinin, in agreement with significant co-expression of mRNA transcripts by single-cell qualitative real-time polymerase chain reaction for KCNQ subtypes and the B2 bradykinin receptor in retrogradely labelled extrinsic sensory neurons from the colon. Retigabine also attenuated responses to mechanical stimulation of the bowel following noxious distension (0–80 mmHg) in a concentration-dependent manner, whereas the KV7 blocker XE991 potentiated such responses. In human bowel tissues, KV7.3 and KV7.5 were expressed in neuronal varicosities co-labelled with synaptophysin and CGRP, and retigabine inhibited bradykinin-induced afferent activation in afferent recordings from human colon. We show that KV7 channels contribute to the sensitivity of visceral sensory neurons to noxious chemical and mechanical stimuli in both mouse and human gut tissues. As such, peripherally restricted KV7 openers may represent a viable therapeutic modality for the treatment of gastrointestinal pathologies.