Brierley Stuart M, Page Amanda J, Hughes Patrick A, Adam Birgit, Liebregts Tobias, Cooper Nicole J, Holtmann Gerald, Liedtke Wolfgang, Blackshaw L Ashley
Discipline of Physiology, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, Australia.
Gastroenterology. 2008 Jun;134(7):2059-69. doi: 10.1053/j.gastro.2008.01.074. Epub 2008 Jan 31.
BACKGROUND & AIMS: Although there are many candidates as molecular mechanotransducers, so far there has been no evidence for molecular specialization of visceral afferents. Here, we show that colonic afferents express a specific molecular transducer that underlies their specialized mechanosensory function: the transient receptor potential channel, vanilloid 4 (TRPV4).
We found TRPV4 mRNA is highly enriched in colonic sensory neurons compared with other visceral and somatic sensory neurons. TRPV4 protein was found in colonic nerve fibers from patients with inflammatory bowel disease, and it colocalized in a subset of fibers with the sensory neuropeptide CGRP in mice. We characterized the responses of 8 subtypes of vagal, splanchnic, and pelvic mechanoreceptors.
Mechanosensory responses of colonic serosal and mesenteric afferents were enhanced by a TRPV4 agonist and dramatically reduced by targeted deletion of TRPV4 or by a TRP antagonist. Other subtypes of vagal and pelvic afferents, by contrast, were unaffected by these interventions. The behavioral responses to noxious colonic distention were also substantially reduced in mice lacking TRPV4.
These data indicate that TRPV4 contributes to mechanically evoked visceral pain, with relevance to human disease. In view of its distribution in favor of specific populations of visceral afferents, we propose that TRPV4 may present a selective novel target for the reduction of visceral pain, which is an important opportunity in the absence of current treatments.
尽管有许多分子可作为机械转导分子，但迄今为止，尚无证据表明内脏传入神经存在分子特异性。在此，我们表明结肠传入神经表达一种特定的分子转导分子，该分子是其特殊机械感觉功能的基础：瞬时受体电位香草酸亚型4（TRPV4）。
我们发现与其他内脏和躯体感觉神经元相比，TRPV4 mRNA在结肠感觉神经元中高度富集。在炎症性肠病患者的结肠神经纤维中发现了TRPV4蛋白，并且在小鼠中它与感觉神经肽降钙素基因相关肽（CGRP）在一部分纤维中共定位。我们对迷走神经、内脏神经和盆神经机械感受器的8种亚型的反应进行了表征。
TRPV4激动剂增强了结肠浆膜和肠系膜传入神经的机械感觉反应，而通过靶向缺失TRPV4或使用TRP拮抗剂可使其显著降低。相比之下，迷走神经和盆神经传入神经的其他亚型不受这些干预的影响。在缺乏TRPV4的小鼠中，对有害结肠扩张的行为反应也大幅降低。
这些数据表明TRPV4导致机械诱发的内脏疼痛，与人类疾病相关。鉴于其在特定内脏传入神经群体中的分布，我们提出TRPV4可能是减轻内脏疼痛的一个选择性新靶点，这在目前缺乏有效治疗方法的情况下是一个重要机遇。
