Rac-maninoff and Rho-vel: The symphony of Rho-GTPase signaling at excitatory synapses.
Rac-maninoff and Rho-vel: The symphony of Rho-GTPase signaling at excitatory synapses.
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DOI：
10.1080/21541248.2021.1885264
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发表时间：
2022-01
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神经元之间的突触连接对于人类认知的各个方面都是必不可少的，因此受到极其精确的调节。rho家族gtpase是一种在活性gtp结合状态和非活性gdp结合状态之间循环的分子开关，是突触调节的一个关键特征。rho - gtpase由一系列激活剂（gef）和抑制剂（gap和gdi）精细控制，并与许多不同的信号通路相互作用，以实现其在协调中枢神经系统兴奋性突触的发育，维持和可塑性中的作用。控制Rho-GTPase活性和信号传导的机制包括细胞表面受体、紧密调节单个Rho-GTPase动力学的GEF/GAP复合物、协调多个rho家族GTPase活性的GEF/GAP和GEF/GEF功能复合物、效应正反馈回路以及相互拮抗的Rho-GTPase途径。这些复杂的调节机制在神经系统细胞发育的几乎每一步中都被使用，并且在突触可塑性的过程中占有突出地位，而突触可塑性是学习和记忆的基础。最后，rho - gtpase的错误调控在神经元损伤（如创伤性脑损伤和神经性疼痛）以及神经发育和神经退行性疾病（包括智力残疾、自闭症谱系障碍、精神分裂症和阿尔茨海默病）的反应中起着关键作用。因此，破译Rho-GTPase在兴奋性突触中的调节机制和功能，对于对抗当前心理健康领域的许多最大挑战具有巨大的潜力。
Synaptic connections between neurons are essential for every facet of human cognition and are thus regulated with extreme precision. Rho-family GTPases, molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state, comprise a critical feature of synaptic regulation. Rho-GTPases are exquisitely controlled by an extensive suite of activators (GEFs) and inhibitors (GAPs and GDIs) and interact with many different signalling pathways to fulfill their roles in orchestrating the development, maintenance, and plasticity of excitatory synapses of the central nervous system. Among the mechanisms that control Rho-GTPase activity and signalling are cell surface receptors, GEF/GAP complexes that tightly regulate single Rho-GTPase dynamics, GEF/GAP and GEF/GEF functional complexes that coordinate multiple Rho-family GTPase activities, effector positive feedback loops, and mutual antagonism of opposing Rho-GTPase pathways. These complex regulatory mechanisms are employed by the cells of the nervous system in almost every step of development, and prominently figure into the processes of synaptic plasticity that underlie learning and memory. Finally, misregulation of Rho-GTPases plays critical roles in responses to neuronal injury, such as traumatic brain injury and neuropathic pain, and in neurodevelopmental and neurodegenerative disorders, including intellectual disability, autism spectrum disorder, schizophrenia, and Alzheimer’s Disease. Thus, decoding the mechanisms of Rho-GTPase regulation and function at excitatory synapses has great potential for combatting many of the biggest current challenges in mental health.