Integrin-KCNB1 potassium channel complexes regulate neocortical neuronal development and are implicated in epilepsy.
Integrin-KCNB1 potassium channel complexes regulate neocortical neuronal development and are implicated in epilepsy.
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DOI：
10.1038/s41418-022-01072-2
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发表时间：
2023-03
影响因子：
12.4
通讯作者：
Sesti, Federico
中科院分区：
文献类型：
--
作者：
Bortolami, Alessandro;Yu, Wei;Forzisi, Elena;Ercan, Koray;Kadakia, Ritik;Murugan, Madhuvika;Fedele, Denise;Estevez, Irving;Boison, Detlev;Rasin, Mladen-Roko;Sesti, Federico
钾 (K+) 通道在产前大脑发育过程中强烈表达，包括在祖细胞和迁移神经元中，但对其功能知之甚少。在这里，我们研究了电压门控 K+ 通道 KCNB1 (Kv2.1) 在新皮质发育中的作用。 KCNB1 缺失小鼠的新皮质中谷氨酸能神经元的神经元迁移受损。迁移缺陷持续存在于成人大脑中，同时形态和突触连接也受到破坏。小鼠出现癫痫表型、焦虑和强迫行为。为了确定 KCNB1 缺陷是否会引起发育性通道病，我们构建了敲入 (KI) 小鼠，其携带在患有发育性脑病和癫痫性脑病 (DEE) 的儿童中发现的基因变异 Kcnb1R312H（R312H 小鼠）。 R312H 小鼠表现出与无效小鼠相似的表型。野生型 (WT) 和 R312H KCNB1 通道与整合素 α5β5 形成复合物（Integrin_K+通道_复合物，IKC），其生化信号在 R312H 大脑中受损。体外血管紧张素 II 治疗纠正了神经元异常，血管紧张素 II 是粘着斑激酶（IKC 信号传导机制的关键组成部分）的激动剂。因此，K+通道的基因突变通过非传导机制诱发严重的神经形态异常，可以通过药物干预来挽救。这强调了 IKC 作为神经元发育中关键参与者的先前未知的作用，并暗示 DEE 病因学中存在发育性通道病。
Potassium (K+) channels are robustly expressed during prenatal brain development, including in progenitor cells and migrating neurons, but their function is poorly understood. Here, we investigate the role of voltage-gated K+ channel KCNB1 (Kv2.1) in neocortical development. Neuronal migration of glutamatergic neurons was impaired in the neocortices of KCNB1 null mice. Migratory defects persisted into the adult brains, along with disrupted morphology and synaptic connectivity. Mice developed seizure phenotype, anxiety, and compulsive behavior. To determine whether defective KCNB1 can give rise to developmental channelopathy, we constructed Knock In (KI) mice, harboring the gene variant Kcnb1R312H (R312H mice) found in children with developmental and epileptic encephalopathies (DEEs). The R312H mice exhibited a similar phenotype to the null mice. Wild type (WT) and R312H KCNB1 channels made complexes with integrins α5β5 (Integrin_K+ channel_Complexes, IKCs), whose biochemical signaling was impaired in R312H brains. Treatment with Angiotensin II in vitro, an agonist of Focal Adhesion kinase, a key component of IKC signaling machinery, corrected the neuronal abnormalities. Thus, a genetic mutation in a K+ channel induces severe neuromorphological abnormalities through non-conducting mechanisms, that can be rescued by pharmacological intervention. This underscores a previously unknown role of IKCs as key players in neuronal development, and implicate developmental channelopathies in the etiology of DEEs.
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影响因子：
2
作者：
de Kovel, Carolien G. F.;Brilstra, Eva H.;van Kempen, Marjan J. A.;van't Slot, Ruben;Nijman, Isaac J.;Afawi, Zaid;De Jonghe, Peter;Djemie, Tania;Guerrini, Renzo;Hardies, Katia;Helbig, Ingo;Hendrickx, Rik;Kanaan, Moine;Kramer, Uri;Lehesjoki, Anna-Elina E.;Lemke, Johannes R.;Marini, Carla;Mei, Davide;Moller, Rikke S.;Pendziwiat, Manuela;Stamberger, Hannah;Suls, Arvid;Weckhuysen, Sarah;Koeleman, Bobby P. C.
通讯作者：
Koeleman, Bobby P. C.
DOI：
10.1146/annurev-cellbio-101512-122400
发表时间：
2013
影响因子：
11.3
作者：
Evsyukova I;Plestant C;Anton ES
通讯作者：
Anton ES
影响因子：
1.5
作者：
Chen VS;Morrison JP;Southwell MF;Foley JF;Bolon B;Elmore SA
通讯作者：
Elmore SA
影响因子：
8.8
作者：
Bird, Alex D.;Cuntz, Hermann
通讯作者：
Cuntz, Hermann
DOI：
10.1073/pnas.0509032102
发表时间：
2005-12-06
影响因子：
11.1
作者：
Chen, JG;Rasin, MR;Sestan, N
通讯作者：
Sestan, N