Tejada-Simon Maria V
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas, USA.
Department of Biology, University of Houston, Houston, Texas, USA.
J Neurochem. 2015 Jun;133(6):767-79. doi: 10.1111/jnc.13100. Epub 2015 Apr 22.
The small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in cells. Formation of extensions at the surface of the cell is required for migration and even for cell invasion and metastases. Because an elevated level and hyperactivation of this protein has been associated with metastasis in cancer, direct regulators of Rac1 are currently envisioned as a potential strategy to treat certain cancers. Less research, however, has been done regarding the role of this small GTP-binding protein in brain development, where it has an important role in dendritic spine morphogenesis through the regulation of actin. Alteration of dendritic development and spinogenesis has been often associated with mental disorders. Rac1 is associated with and required for learning and the formation of memories in the brain. Rac1 appears to be dysregulated in certain neurodevelopmental disorders that present all these three alterations: mental retardation, atypical synaptic plasticity and aberrant spine morphology. Thus, to develop novel therapies for rescuing cognitive impairment, a reasonable approach might be to target this protein, Rac1, which plays a pivotal role in directing signals that regulate actin dynamics, which in turn might have an effect in spine cytoarchitecture and synaptic function. It is possible that novel drugs that regulate Rac1 activation and function could modulate actin cytoskeleton and spine dynamics, representing potential candidates to repair intellectual disability in disorders associated with spine abnormalities. Herein, we present a list of the current Rac1 inhibitors that might fulfill this role together with a summary of the latest findings concerning their function as they relate to neuronal studies. While the small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in different type of cells, it appears to be also required for learning and the formation of memories in the brain. Abnormal regulation of this protein has been associated with cognitive disabilities, atypical synaptic plasticity and abnormal morphology of dendritic spines in certain neurodevelopmental disorders. Thus, modulation of Rac1 activity using novel inhibitors might be a strategy to reestablish cognitive function.
小GTP酶Rac1以调节细胞中的肌动蛋白细胞骨架重组而闻名。细胞表面形成突起对于细胞迁移甚至细胞侵袭和转移都是必需的。由于该蛋白水平升高和过度激活与癌症转移有关，因此Rac1的直接调节剂目前被视为治疗某些癌症的潜在策略。然而，关于这种小GTP结合蛋白在大脑发育中的作用的研究较少，它通过调节肌动蛋白在树突棘形态发生中起重要作用。树突发育和棘形成的改变常与精神障碍有关。Rac1与大脑中的学习和记忆形成有关且是必需的。在某些呈现出所有这三种改变的神经发育障碍中，Rac1似乎失调：智力迟钝、非典型突触可塑性和异常的棘形态。因此，为了开发挽救认知障碍的新疗法，一种合理的方法可能是靶向这种蛋白Rac1，它在指导调节肌动蛋白动力学的信号中起关键作用，这反过来可能对棘细胞结构和突触功能产生影响。调节Rac1激活和功能的新型药物有可能调节肌动蛋白细胞骨架和棘动力学，代表了修复与棘异常相关疾病中智力残疾的潜在候选药物。在此，我们列出了当前可能发挥这一作用的Rac1抑制剂清单，并总结了有关它们与神经元研究相关功能的最新发现。虽然小GTP酶Rac1以调节不同类型细胞中的肌动蛋白细胞骨架重组而闻名，但它似乎也是大脑中学习和记忆形成所必需的。在某些神经发育障碍中，该蛋白的异常调节与认知障碍、非典型突触可塑性和树突棘异常形态有关。因此，使用新型抑制剂调节Rac1活性可能是恢复认知功能的一种策略。
