TRPV4: En RhoA To a Cure?
TRPV4: En RhoA To a Cure?
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DOI：
10.1002/bies.202200071
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发表时间：
2022-06
期刊：
影响因子：
4
通讯作者：
Chen, Yan-Hua
中科院分区：
文献类型：
--
作者：
Lu, Qun;Chen, Yan-Hua
TRPV 4（瞬时受体电位香草酸4）的显性突变在神经系统和骨骼疾病中被广泛认为是通道病谱系疾病。因此，TRPV 4作为治疗这些疾病的潜在治疗靶点被深入研究也就不足为奇了。不幸的是，仍然缺乏有效的治疗选择。尽管已知TRPV 4不同结构域的不同突变簇可能导致不同疾病，但TRPV 4突变与疾病病理学的偶联机制的研究仍在进行中。在这些潜在的机制中，钙超载诱导的毒性和细胞死亡，基因表达和神经突发生失调，以及改变蛋白质-蛋白质相互作用和通道trafficking.In这个问题的BioEssays，出现了一个新的假说，是基于最近的研究，证明了TRPV 4与小GTTRO RhoA的直接物理和双向功能相互作用。TRPV 4神经病变突变引起的相互作用缺陷可导致RhoA的激活和与神经突变性相关的肌动蛋白细胞骨架的重组。RhoA信号传导抑制在体外和TRPV 4神经病的苍蝇模型中恢复了神经突长度。TRPV 4在调节细胞骨架中的功能可以独立于离子通道活性而发生。因此，提出TRPV 4作为RhoGDI和RhoA一起构成环境敏感的信号传导复合物，其有助于神经损伤和疾病期间的病理性细胞骨架改变。由于许多与过度RhoA信号传导相关的相同神经系统疾病也与TRPV 4活化增加相关，因此该假设得出结论，TRPV 4-RhoA抑制是治疗神经系统疾病的有希望的治疗途径[1]。
Widely recognized in channelopathy spectrum disorders, dominant mutations in TRPV4 (transient receptor potential vanilloid 4) have been found in both nervous system and skeletal diseases. It is thus no wonder TRPV4 has been investigated intensely as a potential therapeutic target in treating these disorders. Unfortunately, effective treatment options are still lacking. Although it is known that different clusters of mutations at different domains of TRPV4 are likely causative to different diseases, studies of mechanisms coupling mutations in TRPV4 to disease pathology are still ongoing. Among the potential mechanisms, calcium overload-induced toxicity and cell death, dysregulated gene expression and neuritogenesis, as well as altered protein-protein interactions and channel trafficking have been proposed.In this issue of BioEssays, a new hypothesis emerged that was based on the recent studies which demonstrated the direct physical and bidirectional functional interactions of TRPV4 with small GTPase RhoA. The defective interactions due to TRPV4 neuropathy mutations can lead to an activation of RhoA and reorganization of the actin cytoskeleton associated with neurite degeneration. RhoA signaling inhibition restored neurite length in vitro and in a fly model of TRPV4 neuropathy. The function of TRPV4 in regulating the cytoskeleton can occur independent of ion channel activity. Thus, it was proposed that TRPV4, acting as a RhoGDI, and RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cytoskeletal alterations during neurological injury and disease. As many of the same neurological diseases associated with excessive RhoA signaling are also associated with increased TRPV4 activation, this hypothesis concluded that TRPV4-RhoA inhibition is a promising therapeutic route to treat neurological diseases [1].
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