Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94066, USA.
Curr Top Med Chem. 2011;11(17):2216-26. doi: 10.2174/156802611796904861.
TRPV4 belongs to the TRPV subfamily of Transient Receptor Potential (TRP) ion channels. This year marks the 10 year anniversary of the discovery of this polymodal ion channel which is activated by a variety of stimuli including warm temperatures, hypotonicity and endogenous lipids. Coupled with a widespread tissue distribution, this activation profile has resulted in a large number of disparate physiological functions for TRPV4. These range from temperature monitoring in skin keratinocytes to osmolarity sensing in kidneys, sheer stress detection in blood vessels and osteoclast differentiation control in bone. As knowledge of its physiological roles has expanded, interest in targeting TRPV4 modulation for therapeutic purposes has arisen and is now focused on several areas. First, as with related TRP channels TRPV1, TRPV3, TRPM8 and TRPA1, TRPV4 antagonism is being considered for inflammatory and neuropathic pain treatment. Recent work conducted using KO mice and agonists 4αPDD and GSK1016790A suggests bladder dysfunctions may also be targeted. Additionally, ventilator-induced lung injury has emerged as another potential indication for TRPV4 antagonists. Herein we review the known small molecule modulators of TRPV4 and relate progress made in identifying potent, selective and bioavailable agonists and antagonists to interrogate this ion channel in vivo.
TRPV4 属于瞬时受体电位 (TRP) 离子通道的 TRPV 亚家族。今年是发现这种多模式离子通道的 10 周年，该通道可被多种刺激激活，包括温暖的温度、低渗性和内源性脂质。再加上广泛的组织分布，这种激活模式导致 TRPV4 具有许多不同的生理功能。这些功能范围从皮肤角质形成细胞中的温度监测到肾脏中的渗透压感应，血管中的纯应切力检测以及骨骼中的破骨细胞分化控制。随着对其生理作用的认识不断扩大，人们对 TRPV4 调节的靶向治疗产生了兴趣，目前主要集中在几个领域。首先，与相关的 TRP 通道 TRPV1、TRPV3、TRPM8 和 TRPA1 一样，TRPV4 拮抗剂也被认为可用于治疗炎症性和神经性疼痛。最近使用 KO 小鼠和激动剂 4αPDD 和 GSK1016790A 进行的研究表明，膀胱功能障碍也可能成为靶点。此外，呼吸机诱导的肺损伤也成为 TRPV4 拮抗剂的另一个潜在适应症。本文综述了已知的 TRPV4 小分子调节剂，并介绍了在鉴定有效、选择性和可生物利用的激动剂和拮抗剂以在体内研究该离子通道方面所取得的进展。
