Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology (EFAR), Center for Neurosciences (C4N), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Biomolecules. 2020 Nov 20;10(11):1578. doi: 10.3390/biom10111578.
In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments.
在癫痫研究中，重点是探索非神经元靶点，如星形胶质细胞蛋白，因为许多患者对目前几乎所有针对神经元机制的治疗仍然耐药。本文综述了星形胶质细胞缝隙连接蛋白 43（Cx43）在癫痫发作和癫痫中的信号转导的现有数据。Cx43 是一种广泛表达的跨膜蛋白，是间隙连接（GJ）和半通道（HC）的组成部分，分别允许细胞间和细胞外通讯。大量研究论文表明，在人类癫痫组织和实验模型中，Cx43 的 mRNA 水平、蛋白表达、磷酸化状态、分布和/或功能偶联发生改变。人类 Cx43 突变也与癫痫有关，因为 30%的眼齿指发育不良（ODDD）患者，一种由编码 Cx43 蛋白的 GJA1 基因突变引起的罕见遗传疾病，表现出包括癫痫发作在内的神经症状。Cx30/Cx43 双敲除小鼠由于 GJ 介导的钾和谷氨酸再分布受损，在脑片上易发生诱发癫痫样事件，并在癫痫模型中显示出更高频率的自发性全身性慢性癫痫发作。相反，Cx30/Cx43 GJ 可以将营养物质运送到高能量需求的神经元，并引发星形胶质细胞 Ca 波和超同步，从而支持促惊厥作用。一般的缝隙连接通道阻滞剂 carbenoxolone 和来自芬那酸家族的阻滞剂在体外减少癫痫样活动，并改善体内癫痫发作的结果。此外，具有 HC 更选择性肽抑制剂的干预措施显示出抗惊厥作用。总之，进一步研究旨在阐明 HC 和 GJ 的不同作用是必要的，并且专门针对 Cx43 HC 的工具可能有助于寻找新的癫痫治疗方法。
