Department of Neurosurgery, Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, Chongqing, China.
Department of Endoscopy center, Chongqing Jiangjin District Hospital of Traditional Chinese Medicine, Chongqing, China.
Neurosci Res. 2022 Sep;182:7-14. doi: 10.1016/j.neures.2022.05.006. Epub 2022 May 21.
Disruption of γ-aminobutyric acid type A receptors (GABARs) synaptic clustering and a decrease number in the plasma membrane are thought to contribute to the alteration in the balance between excitatory and inhibitory neurotransmission in the epilepsy. Thus, it is important to elucidate the molecular mechanisms that regulate the stabilities of surface GABARs populations as well as their concentrations at inhibitory synapses. However, the mechanism that delivers GABARs to plasma membrane has not been conclusively determined. Our previous research indicated that huntingtin-associated protein 1 (HAP1), a major facilitator of pathological variations in membrane trafficking, modulates epileptic seizure by regulating GABARs-mediated inhibitory synaptic transmission in pentylenetetrazole (PTZ)-induced epileptic rats. However, a detailed molecular interaction networks comprising GABARs and HAP1 is necessary for studying and investigating new treatment targets for epilepsy. In this study, we indicate that HAP1 specifically interacts with 14-3-3, a protein that functions as a chaperone, forming a cargo adaptor complex to regulate surface GABARs expression and the inhibitory post-synaptic current amplitudes. Disrupting the HAP1/14-3-3 complex decreases the strength of GABAARs-mediated inhibitory synaptic transmission in epilepsy. Taken together, HAP1/14-3-3 complex is linked to inhibitory synaptic transmission in evoking seizures, therefore, it is a possible drug target for epilepsy.
γ-氨基丁酸 A 型受体 (GABARs) 突触聚集的破坏和质膜数量的减少被认为导致癫痫症中兴奋性和抑制性神经递质传递之间的平衡改变。因此，阐明调节表面 GABARs 群体稳定性及其在抑制性突触处浓度的分子机制非常重要。然而，将 GABARs 递送到质膜的机制尚未得到明确确定。我们之前的研究表明，亨廷顿相关蛋白 1 (HAP1) 是膜运输病理性变化的主要促进剂，通过调节戊四氮 (PTZ) 诱导的癫痫大鼠中 GABARs 介导的抑制性突触传递来调节癫痫发作。然而，研究和调查癫痫新治疗靶点需要包括 GABARs 和 HAP1 的详细分子相互作用网络。在这项研究中，我们表明 HAP1 特异性地与 14-3-3 相互作用，14-3-3 是一种作为伴侣蛋白发挥作用的蛋白质，形成货物衔接复合物以调节表面 GABARs 表达和抑制性突触后电流幅度。破坏 HAP1/14-3-3 复合物会降低癫痫症中 GABAARs 介导的抑制性突触传递的强度。总之，HAP1/14-3-3 复合物与癫痫发作中抑制性突触传递有关，因此，它可能是治疗癫痫的药物靶点。
