Structural insights into the TRPV4-RhoA complex offer clues to solve the puzzle of TRPV4 channelopathies.
Structural insights into the TRPV4-RhoA complex offer clues to solve the puzzle of TRPV4 channelopathies.
复制标题
对 TRPV4-RhoA 复合物的结构了解为解决 TRPV4 通道病之谜提供了线索。
DOI：
10.1016/j.ceca.2023.102814
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发表时间：
2023
期刊：
影响因子：
4
通讯作者：
Hu,Hongzhen
中科院分区：
文献类型：
--
作者：
Hu,Xueming;Hu,Hongzhen
瞬时受体电位香草酸4型（TRPV 4）属于TRP（瞬时受体电位）离子通道家族，在全身各种细胞类型中表达。在被内源性配体和各种外源性刺激（如机械力、温暖的温度、渗透压和各种化学物质）激活后，TRPV 4作为非选择性阳离子通道发挥作用，促进钙、钠和其他阳离子跨细胞膜的转运。TRPV 4是许多细胞反应和生理效应的重要组成部分[1]。TRPV 4抑制正在成为一种有趣的治疗方法，因为与TRPV 4通道功能获得相关的基因突变与多种疾病和疾病有关，这些疾病和疾病表现出各种临床症状[2]。RhoA是一种小的GTP酶蛋白，作为分子开关，在活性的GTP结合状态和非活性的GDP结合状态之间交替，以动态调节细胞过程。最近的研究已经确定RhoA作为TRPV 4的直接相互作用物，其抑制TRPV 4离子通道功能。TRPV 4-RhoA相互作用的破坏可能有助于引起神经病的TRPV 4突变的病理作用[3，4]。尽管热带爪蟾TRPV 4的初始Cryo-EM和X射线结构提供了对TRPV 4的离子渗透和门控机制的见解[5]，但人TRPV 4-RhoA复合物的功能和结构表征在很大程度上仍然未知。
The transient receptor potential vanilloid type 4 (TRPV4), which belongs to the TRP (transient receptor potential) ion channel family, is expressed in various cell types throughout the body. After being activated by endogenous ligands and various exogenous stimuli, such as mechanical forces, warm temperatures, osmotic pressure, and various chemicals, TRPV4 functions as a nonselective cation channel that facilitates the transport of calcium, sodium, and other cations across the cell membrane. TRPV4 is an essential component of numerous cellular responses and physiological effects [1].TRPV4 inhibition is emerging as an intriguing therapeutic approach because genetic mutations related to the gain-of-function of the TRPV4 channel have been linked to multiple diseases and ailments, which present a variety of clinical symptoms [2]. RhoA is a small GTPase protein that functions as a molecular switch, alternating between an active, GTP-bound state and an inactive, GDP-bound state, in order to dynamically regulate cellular processes. Recent studies have identified RhoA as a direct interactor of TRPV4, which suppresses TRPV4 ion channel function. Disruption of the TRPV4-RhoA interaction may contribute to the pathological effects of neuropathy-causing TRPV4 mutations [3, 4]. Although the initial Cryo-EM and X-ray structures of Xenopus tropicalis TRPV4 provide insights into the ion permeation and gating mechanisms of TRPV4 [5], the functional and structural characterization of the human TRPV4-RhoA complex is still largely unknown.