[1]冯兰兰,高学军,马磊.星形胶质细胞连接蛋白43在癫痫中的研究进展[J].中国临床神经外科杂志,2024,29(11):690-695.[doi:10.13798/j.issn.1009-153X.2024.11.012]
 FENG Lan-lan,GAO Xue-jun,MA Lei.Research advances of connexin 43 in astrocytes in epilepsy[J].,2024,29(11):690-695.[doi:10.13798/j.issn.1009-153X.2024.11.012]
点击复制

星形胶质细胞连接蛋白43在癫痫中的研究进展()
分享到:

《中国临床神经外科杂志》[ISSN:1009-153X/CN:42-1603/TN]

卷:
29
期数:
2024年11期
页码:
690-695
栏目:
综述
出版日期:
2024-11-30

文章信息/Info

Title:
Research advances of connexin 43 in astrocytes in epilepsy
文章编号:
1009-153X(2024)11-0690-06
作者:
冯兰兰高学军马磊
716000陕西延安,延安大学医学院(冯兰兰);710032西安,空军军医大学第一附属医院神经内科(冯兰兰、马磊);716000陕西延安,延安大学附属医院神经内科(高学军)
Author(s):
FENG Lan-lan12 GAO Xue-jun3 MA Lei2
1. Medical College of Yan'an University, Yan'an 716000, China; 2. Department of Neurology, The First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China; 3. Department of Neurology, The Affiliated Hospital of Yan 'an University, Yan'a
关键词:
癫痫星形胶质细胞连接蛋白43缝隙连接半通道
Keywords:
Epilepsy Astrocyte Connexin 43 Gap junctions Hemichannels
分类号:
R 742.1
DOI:
10.13798/j.issn.1009-153X.2024.11.012
文献标志码:
A
摘要:
连接蛋白43(CX43)是一种广泛表达的跨膜蛋白,通过缝隙连接(GJCs)和半通道(HCs)两种方式参与中枢神经系统的功能调节,使星形胶质细胞和神经元之间形成功能和代谢的偶联。GJCs主要介导细胞间的通讯,HCs介导胞内与胞外的物质交换。无论是癫痫病人致痫灶组织切片,还是癫痫动物模型组织切片,星形胶质细胞CX43的表达和功能偶联都发生改变。GJCs减少和HCs过度激活在癫痫的发生、同步和维持中发挥重要作用。癫痫动物模型研究发现,星形胶质细胞CX43的阻断剂可改善癫痫发作。这提示星形胶质细胞CX43可能是控制癫痫发作的一个新的治疗靶点。本文主要对星形胶质细胞CX43在癫痫中作用展开综述。
Abstract:
Connexin 43 (CX43), a transmembrane protein ubiquitously present in the central nervous system, participates in the functional and metabolic coupling between neurons and astrocytes via two pathways, namely gap junction channels (GJCs) and hemichannels (HCs). GJCs primarily account for direct intercellular communication, while HCs mediate the exchange of substances between the intracellular and extracellular milieus. Research indicates that in tissue sections of epileptic foci from patients with epilepsy and in animal models of epilepsy, both the expression pattern and functional coupling of CX43 have undergone marked alterations. Specifically manifested as a reduction in the quantity of GJCs and excessive activation of HCs, these changes play a crucial role in the genesis, development, and perpetuation of epilepsy. Further studies have revealed that the application of CX43 blockers can effectively ameliorate the symptoms of epileptic seizures, suggesting that CX43 might be a potential therapeutic target for controlling epileptic seizures. This article aims to review the role of CX43 in astrocytes in the pathological mechanism of epilepsy and its potential as a therapeutic target.

参考文献/References:

[1] FIEST KM, SAURO KM, WIEBE S, et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies [J]. Neurology, 2017, 88(3): 296-303.
[2] CHEN Z, BRODIE MJ, LIEW D, et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study [J]. JAMA Neurol, 2018, 75(3): 279-286.
[3] BINDER DK, STEINHAUSER C. Astrocytes and epilepsy [J]. Neurochem Res, 2021, 46(10): 2687-2695.
[4] GIAUME C, NAUS CC, SáEZ JC, et al. Glial connexins and pannexins in the healthy and diseased brain [J]. Physiol Rev, 2021, 101 (1): 93-145.
[5] NARDIN C, MAMMANO F. Measurement of Ca(2+) uptake through connexin hemichannels [J]. Methods Mol Biol, 2024, 2801: 97-109.
[6] DE BOCKM, KERREBROUCK M, WANG N, et al. Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system [J]. Front Pharmacol, 2013, 4: 55296.
[7] DELVAEYE T, VANDENABEELE P, BULTYNCK G, et al. Therapeutic targeting of connexin channels: new views and challenges [J]. Trends Mol Med, 2018, 24(12): 1036-1053.
[8] LEE HJ, JEONG H, HYUN J, et al. Cryo-EM structure of human Cx31.3/GJC3 connexin hemichannel [J]. Sci Adv, 2020, 6(35): eaba4996.
[9] NAULIN PA, LOZANO B, FUENTES C, et al. Polydisperse molecular architecture of connexin 26/30 heteromeric hemichannels revealed by atomic force microscopy imaging [J]. J Biol Chem, 2020, 295 (49): 16499-16509.
[10] SARROUILHE D, DEJEAN C, MESNIL M. Connexin43- and pannexin-based channels in neuroinflammation and cerebral neuropathies [J]. Front Mol Neurosci, 2017, 10: 320.
[11] STEHBERG J, MORAGA-AMARO R, SALAZAR C, et al. Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala [J]. Faseb J, 2012, 26(9): 3649-3657.
[12] ORELLANA JA, MORAGA-AMARO R, DíAZ-GALARCE R, et al. Restraint stress increases hemichannel activity in hippocampal glial cells and neurons [J]. Front Cell Neurosci, 2015, 9: 102.
[13] MEUNIER C, WANG N, YIC, et al. Contribution of astroglial Cx43 hemichannels to the modulation of glutamatergic currents by Dserine in the mouse prefrontal cortex [J]. J Neurosci, 2017, 37(37): 9064-9075.
[14] BENNETT MV, CONTRERAS JE, BUKAUSKAS FF, et al. New roles for astrocytes: gap junction hemichannels have something to communicate [J]. Trends Neurosci, 2003, 26(11): 610-617.
[15] NAUS CC, BECHBERGER JF, PAUL DL. Gap junction gene expression in human seizure disorder [J]. Exp Neurol, 1991, 111(2): 198-203.
[16] WALRAVE L, VINKEN M, LEYBAERT L, et al. Astrocytic connexin43 channels as candidate targets in epilepsy treatment [J]. Biomolecules, 2020, 10(11): 1578.
[17] ZHANG M, WANG ZZ, CHEN NH. Connexin 43 phosphorylation: implications in multiple diseases [J]. Molecules, 2023, 28(13): 4914.
[18] DESHPANDE T, LI T, HERDE MK, et al. Subcellular reorganization and altered phosphorylation of the astrocytic gap junction protein connexin43 in human and experimental temporal lobe epilepsy [J]. Glia, 2017, 65(11): 1809-1820.
[19] DU Y, LI R, FU D, et al. Multi-omics technologies and molecular biomarkers in brain tumor-related epilepsy [J]. CNS Neurosci Ther, 2024, 30(4): e14717.
[20] DONG H, ZHOU XW, WANG X, et al. Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma-associated epileptic discharge [J]. Mol Med Report, 2017, 16(6): 7890-7900.
[21] CHE J, DEPALMA TJ, SIVAKUMAR H, et al. αCT1 peptide sensitizes glioma cells to temozolomide in a glioblastoma organoid platform [J]. Biotechnol Bioeng, 2023, 120(4): 1108-1119.
[22] BARACALDO-SANTAMARíA D, CORRALES-HERNáNDEZ MG, ORTIZ-VERGARA M C, et al. Connexins and pannexins: important players in neurodevelopment, neurological diseases, and potential therapeutics [J]. Biomedicines, 2022, 10(9): 2237.
[23] MOTAGHI S, SAYYAH M, BABAPOUR V, et al. Hippocampal expression of connexin36 and connexin43 during epileptogenesis in pilocarpine model of epilepsy [J]. Iran Biomed J, 2017, 21(3): 167-173.
[24] LIU B, RAN X, YI Y, et al. Anticonvulsant effect of carbenoxolone on chronic epileptic rats and its mechanism related to connexin and high-frequency oscillations [J]. Front Mol Neurosci, 2022, 15: 870947.
[25] ANDRIOLI A, FABENE PF, MUDò G, et al. Downregulation of the astroglial connexin expression and neurodegeneration after pilocarpine-induced status epilepticus [J]. Int J Mol Sci, 2022, 24(1): 23.
[26] ALTAS B, RHEE HJ, JU A, et al. Nedd4-2-dependent regulation of astrocytic Kir4.1 and connexin43 controls neuronal network activity [J]. J Cell Biol, 2024, 223(1): e201902050.
[27] MEN C, WANG Z, ZHOU L, et al. Transient receptor potential vanilloid 4 is involved in the upregulation of connexin expression following pilocarpine-induced status epilepticus in mice [J]. Brain Res Bull, 2019, 152: 128-133.
[28] BREITHAUSEN B, KAUTZMANN S, BOEHLEN A, et al. Limited contribution of astroglial gap junction coupling to buffering of extracellular K(+) in CA1 stratum radiatum [J]. Glia, 2020, 68(5): 918-931.
[29] ROSE CR, FELIX L, ZEUG A, et al. Astroglial glutamate signaling and uptake in the hippocampus [J]. Front Mol Neurosci, 2017, 10: 451.
[30] RIQUELME J, WELLMANN M, SOTOMAYOR-ZARATE R, et al. Gliotransmission: a novel target for the development of antiseizure drugs [J]. Neuroscientist, 2020, 26(4): 293-309.
[31] MULLER J, TIMMERMANN A, HENNING L, et al. Astrocytic GABA accumulation in experimental temporal lobe epilepsy [J]. Front Neurol, 2020, 11: 614923.
[32] HOSLI L, BININI N, FERRARI KD, et al. Decoupling astrocytes in adult mice impairs synaptic plasticity and spatial learning [J]. Cell Rep, 2022, 38(10): 110484.
[33] PHILIPPOT C, GRIEMSMANN S, JABS R, et al. Astrocytes and oligodendrocytes in the thalamus jointly maintain synaptic activity by supplying metabolites [J]. Cell Rep, 2021, 34(3): 108642.
[34] HENNEBERGER C. Does rapid and physiological astrocyte-neuron signalling amplify epileptic activity [J]. J Physiol, 2017, 595(6): 1917-1927.
[35] GIGOUT S, LOUVEL J, RINALDI D, et al. Thalamocortical relationships and network synchronization in a new genetic model "in mirror" for absence epilepsy [J]. Brain Res, 2013, 1525: 39-52.
[36] CHANG WP, WU JJ, SHYU BC. Thalamic modulation of cingulate seizure activity via the regulation of gap junctions in mice thalamocingulate slice [J]. PLoS One, 2013, 8(5): e62952.
[37] ROSS FM, GWYN P, SPANSWICK D, et al. Carbenoxolone depresses spontaneous epileptiform activity in the CA1 region of rat hippocampal slices [J]. Neuroscience, 2000, 100(4): 789-796.
[38] GIGOUT S, LOUVEL J, KAWASAKI H, et al. Effects of gap junction blockers on human neocortical synchronization [J]. Neurobiol Dis, 2006, 22(3): 496-508.
[39] VOLNOVA A, TSYTSAREV V, GANINA O, et al. The anti-epileptic effects of carbenoxolone in vitro and in vivo [J]. Int J Mol Sci, 2022, 23(2): 663.
[40] RAN X, XIANG J, SONG PP, et al. Effects of gap junctions blockers on fast ripples and connexin in rat hippocampi after status epilepticus [J]. Epilepsy Res, 2018, 146: 28-35.
[41] GIGOUT S, LOUVEL J, PUMAIN R. Effects in vitro and in vivo of a gap junction blocker on epileptiform activities in a genetic model of absence epilepsy [J]. Epilepsy Res, 2006, 69(1): 15-29.
[42] WU XM, WANG GL, MIAO J, et al. Effect of connexin 36 blockers on the neuronal cytoskeleton and synaptic plasticity in kainic acidkindled rats [J]. Transl Neurosci, 2015, 6(1): 252-258.
[43] BRAGIN A, MODY I, WILSON CL, et al. Local generation of fast ripples in epileptic brain [J]. J Neurosci, 2002, 22(5): 2012-2021.
[44] FRANCO-PéREZ J, BALLESTEROS-ZEBADúA P, MANJARREZMARMOLEJO J. Unilateral microinjection of carbenoxolone into the pontis caudalis nucleus inhibits the pentylenetetrazole-induced epileptiform activity in rats [J]. Neurosci Lett, 2015, 602: 38-43.
[45] MANJARREZ-MARMOLEJO J, FRANCO-PéREZ J. Gap junction blockers: an overview of their effects on induced seizures in animal models [J]. Curr Neuropharmacol, 2016, 14(7): 759-771.
[46] BRAET K, VANDAMME W, MARTIN PE, et al. Photoliberating inositol-1,4,5-trisphosphate triggers ATP release that is blocked by the connexin mimetic peptide gap 26 [J]. Cell Calcium, 2003, 33(1): 37-48.
[47] TORRES A, WANG F, XU Q, et al. Extracellular Ca2+ acts as a mediator of communication from neurons to glia [J]. Sci Signal, 2012, 5(208): ra8-ra8.
[48] SAMOILOVA M, WENTLANDT K, ADAMCHIK Y, et al. Connexin 43 mimetic peptides inhibit spontaneous epileptiform activity in organotypic hippocampal slice cultures [J]. Exp Neurol, 2008, 210 (2): 762-775.
[49] COUTINHO FP, GREEN CR, ACOSTA ML, et al. Xentry-gap19 inhibits connexin43 hemichannel opening especially during hypoxic injury [J]. Drug Deliv Transl Res, 2020, 10(3): 751-765.
[50] WALRAVE L, PIERRE A, ALBERTINI G, et al. Inhibition of astroglial connexin43 hemichannels with TAT-gap19 exerts anticonvulsant effects in rodents [J]. Glia, 2018, 66(8): 1788-1804.
[51] DOBOLYI A, KéKESI KA, JUHáSZ G, et al. Receptors of peptides as therapeutic targets in epilepsy research [J]. Curr Med Chem, 2014, 21(6): 764-787.
[52] GUO A, ZHANG H, LI H, et al. Inhibition of connexin hemichannels alleviates neuroinflammation and hyperexcitability in temporal lobe epilepsy [J]. Proc Natl Acad Sci USA, 2022, 119(45): e2213162119.
[53] LI H, GUO A, SALGADO M, et al. The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice [J]. J Neuroinflammation, 2023, 20(1): 191.
[54] CISTERNA BA, VARGAS AA, PUEBLA C, et al. Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation [J]. Nat Commun, 2020, 11(1): 1073.

相似文献/References:

[1]云德波 杨宇焦 张 逵 范润金 张 渊 杜贻庆.瘤周谷氨酸、天门冬氨酸水平与胶质瘤继发性 癫痫的相关性[J].中国临床神经外科杂志,2016,(06):331.[doi:10.13798/j.issn.1009-153X.2016.06.004]
 YUN De-bo,YANG Yu-Jiao,ZHANG Kui,et al.Relationship of levels of glutamate and aspartate in peritumorous tissues with seizures in patients with gliomas[J].,2016,(11):331.[doi:10.13798/j.issn.1009-153X.2016.06.004]
[2]周长帅 任志伟 综述 遇 涛 李勇杰 审校.岛叶癫痫症状学研究进展周长[J].中国临床神经外科杂志,2016,(04):249.[doi:10.13798/j.issn.1009-153X.2016.04.021]
[3]田春雷 王晓丹 综述 王雄伟 审校.局灶性皮层发育不良与mTOR信号通路[J].中国临床神经外科杂志,2016,(02):122.[doi:10.13798/j.issn.1009-153X.2016.02.025]
[4]黄 河 杜 浩 吕丽辉 宋 健 黄 成 何远志 孙荣辉 丁慧超 黄玲玥 徐国政 马廉亭.影像融合及颅内电极三维重建在癫痫术前计划中的应用[J].中国临床神经外科杂志,2015,(12):705.[doi:10.13798/j.issn.1009-153X.2015.12.001]
 HUANG He,DU Hao,Lü Li-hui,et al.Value of MRI and CT images co-registration and three-dimensional visualization of intracranial electrodes to presurgical planning for epilepsy surgery[J].,2015,(11):705.[doi:10.13798/j.issn.1009-153X.2015.12.001]
[5]孙 拯 谢延风 石全红 但 炜 詹 彦 陆 波 孙晓川.以癫痫起病的幕上脑海绵状血管瘤的治疗[J].中国临床神经外科杂志,2015,(12):709.[doi:10.13798/j.issn.1009-153X.2015.12.002]
 SUN Zheng,XIE Yan-feng,SHI Quan-hong,et al.Treatment of supratentorial cerebral cavernous angioma associated with epilepsy as first symptom[J].,2015,(11):709.[doi:10.13798/j.issn.1009-153X.2015.12.002]
[6]王林林 李宗正.癫痫致呼吸停止1例[J].中国临床神经外科杂志,2015,(06):359.[doi:10.13798/j.issn.1009-153X.2015.06.014]
[7]孙荣辉 徐国政 杜 浩 宋 健 黄 河 赵曰圆 马廉亭.MRI与DSA影像融合联合电生理监测对脑动静脉畸形伴癫痫手术的价值[J].中国临床神经外科杂志,2015,(07):403.[doi:10.13798/j.issn.1009-153X.2015.07.007]
 SUN Rong-hui,XU Guo-zheng,DU Hao,et al.Value of MRI and 3D-DSA images fusion combined with intraoperative neuro-electrophysiological technique to surgery for intracranial arteriovenous malformation associated with epilepsy[J].,2015,(11):403.[doi:10.13798/j.issn.1009-153X.2015.07.007]
[8]陈 旭 吴 琳 冯达云 王举磊 秦怀洲 高国栋 张治国.头孢曲松钠对大鼠蛛网膜下腔出血后认知功能的影响[J].中国临床神经外科杂志,2015,(04):228.[doi:10.13798/j.issn.1009-153X.2015.04.012]
 CHEN Xu,WU Lin,FENG Da-yun,et al.Effect of ceftriaxone on cognitive function after subarachnoid hemorrhage in the adult rats[J].,2015,(11):228.[doi:10.13798/j.issn.1009-153X.2015.04.012]
[9]刘庚勋 综述 李正贤 审校.痫相关低级别中枢神经系统肿瘤的病理学诊断[J].中国临床神经外科杂志,2015,(03):183.[doi:10.13798/j.issn.1009-153X.2015.03.021]
[10]马 炜 张 华 李焕发 王 超 孟 强 刘 备 武 昊.伴有丛集发作的儿童癫痫患者的手术治疗[J].中国临床神经外科杂志,2015,(01):8.[doi:10.13798/j.issn.1009-153X.2015.01.003]
 MA Wei,ZHANG Hua,LI Huan-fa,et al.Surgery for children with epilepsy and seizure clustering (report of 33 cases)[J].,2015,(11):8.[doi:10.13798/j.issn.1009-153X.2015.01.003]

备注/Memo

备注/Memo:
(2023-08-24收稿,2024-07-08修回)
基金项目:国家自然科学基金(82071449)
通信作者:马 磊,Email:malei@fmmu.edu.cn
更新日期/Last Update: 2024-11-30