Darby W G, Grace M S, Baratchi S, McIntyre P
School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia.
School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia; Baker IDI, Melbourne, Australia.
Int J Biochem Cell Biol. 2016 Sep;78:217-228. doi: 10.1016/j.biocel.2016.07.012. Epub 2016 Jul 15.
Transient receptor potential ion channels (TRP) are a superfamily of non-selective ion channels which are opened in response to a diverse range of stimuli. The TRP vanilloid 4 (TRPV4) ion channel is opened in response to heat, mechanical stimuli, hypo-osmolarity and arachidonic acid metabolites. However, recently TRPV4 has been identified as an ion channel that is modulated by, and opened by intracellular signalling cascades from other receptors and signalling pathways. Although TRPV4 knockout mice show relatively mild phenotypes, some mutations in TRPV4 cause severe developmental abnormalities, such as the skeletal dyplasia and arthropathy. Regulated TRPV4 function is also essential for healthy cardiovascular system function as a potent agonist compromises endothelial cell function, leading to vascular collapse. A better understanding of the signalling mechanisms that modulate TRPV4 function is necessary to understand its physiological roles. Post translational modification of TRPV4 by kinases and other signalling molecules can modulate TRPV4 opening in response to stimuli such as mechanical and hyposmolarity and there is an emerging area of research implicating TRPV4 as a transducer of these signals as opposed to a direct sensor of the stimuli. Due to its wide expression profile, TRPV4 is implicated in multiple pathophysiological states. TRPV4 contributes to the sensation of pain due to hypo-osmotic stimuli and inflammatory mechanical hyperalsgesia, where TRPV4 sensitizaton by intracellular signalling leads to pain behaviors in mice. In the vasculature, TRPV4 is a regulator of vessel tone and is implicated in hypertension and diabetes due to endothelial dysfunction. TRPV4 is a key regulator of epithelial and endothelial barrier function and signalling to and opening of TRPV4 can disrupt these critical protective barriers. In respiratory function, TRPV4 is involved in cystic fibrosis, cilary beat frequency, bronchoconstriction, chronic obstructive pulmonary disease, pulmonary hypertension, acute lung injury, acute respiratory distress syndrome and cough.In this review we highlight how modulation of TRPV4 opening is a vital signalling component in a range of tissues and why understanding of TRPV4 regulation in the body may lead to novel therapeutic approaches to treating a range of disease states.
瞬时受体电位离子通道（TRP）是一类非选择性离子通道超家族，可响应多种刺激而开放。TRP香草酸受体4（TRPV4）离子通道可因热、机械刺激、低渗和花生四烯酸代谢产物而开放。然而，最近TRPV4已被确定为一种可被其他受体和信号通路的细胞内信号级联调节并开放的离子通道。尽管TRPV4基因敲除小鼠表现出相对较轻的表型，但TRPV4的一些突变会导致严重的发育异常，如骨骼发育不全和关节病。TRPV4功能的正常调节对于健康的心血管系统功能也至关重要，因为强效激动剂会损害内皮细胞功能，导致血管塌陷。更好地理解调节TRPV4功能的信号机制对于了解其生理作用是必要的。激酶和其他信号分子对TRPV4的翻译后修饰可调节TRPV4对机械和低渗性等刺激的开放，并且有一个新兴的研究领域暗示TRPV4是这些信号的转导者，而不是刺激的直接传感器。由于其广泛的表达谱，TRPV4与多种病理生理状态有关。TRPV4导致低渗刺激和炎症性机械性痛觉过敏引起的疼痛感觉，其中细胞内信号传导使TRPV4敏感化会导致小鼠出现疼痛行为。在脉管系统中，TRPV4是血管张力的调节因子，并且由于内皮功能障碍而与高血压和糖尿病有关。TRPV4是上皮和内皮屏障功能的关键调节因子，TRPV4的信号传导和开放会破坏这些关键的保护屏障。在呼吸功能方面，TRPV4参与囊性纤维化、纤毛摆动频率、支气管收缩慢性阻塞性肺疾病、肺动脉高压、急性肺损伤、急性呼吸窘迫综合征和咳嗽。在本综述中，我们强调了TRPV4开放的调节如何在一系列组织中是一个至关重要的信号成分，以及为什么了解体内TRPV4的调节可能会带来治疗一系列疾病状态的新治疗方法。
