Xia Shuting, Zhou Zikai, Jia Zhengping
a The Key Laboratory of Developmental Genes and Human Disease, Southeast University , Nanjing , China.
b Neurosciences and Mental Health Program, the Hospital for Sick Children , Toronto , Canada.
Small GTPases. 2018 Jul 4;9(4):322-326. doi: 10.1080/21541248.2016.1228793. Epub 2016 Sep 20.
The Rho family small GTPases and their effectors, including PAKs, are extensively studied in the context of the actin cytoskeleton, excitatory synaptic function, spine morphology and memory formation. However, their roles in inhibitory synaptic function remain poorly understood. We have recently shown that PAK1 is a potent regulator of GABAergic synaptic transmission. Thus, disruption of PAK1 leads to significant impairments in inhibitory postsynaptic currents which are manifested as reduced GABA presynaptic releases. Interestingly, this effect of PAK1 is distinct from its previously known role in spines and excitatory synaptic transmission in that it is independent of postsynaptic actin, but requires retrograde messengers produced and released from the postsynaptic neurons to suppress presynaptic GABA releases. We have further identified eCBs as the retrograde messengers and shown that PAK1 regulates the eCB signaling via restricting the tissue level of AEA by promoting synaptic expression of COX-2, a key enzyme to oxidize AEA. These results have established a novel pathway whereby PAK1, and by extension Rho proteins, regulates cellular processes, synaptic function and behaviors and have important implications in understanding and treating various diseases linked to PAKs and Rho signaling.
Rho家族小GTP酶及其效应蛋白，包括PAKs，在肌动蛋白细胞骨架、兴奋性突触功能、棘突形态和记忆形成的背景下得到了广泛研究。然而，它们在抑制性突触功能中的作用仍知之甚少。我们最近发现PAK1是GABA能突触传递的有效调节因子。因此，PAK1的破坏会导致抑制性突触后电流出现显著损伤，表现为GABA突触前释放减少。有趣的是，PAK1的这种作用与其先前已知的在棘突和兴奋性突触传递中的作用不同，因为它不依赖于突触后肌动蛋白，而是需要突触后神经元产生和释放的逆行信使来抑制突触前GABA释放。我们进一步确定内源性大麻素（eCBs）为逆行信使，并表明PAK1通过促进COX - 2（一种氧化AEA的关键酶）的突触表达来限制AEA的组织水平，从而调节eCB信号传导。这些结果建立了一条新的途径，通过该途径PAK1以及Rho蛋白可调节细胞过程、突触功能和行为，并且对理解和治疗与PAKs和Rho信号传导相关的各种疾病具有重要意义。
