Molecular mechanisms of voltage-gated potassium channel clustering in myelinated axons

有髓轴突电压门控钾通道聚集的分子机制

• 批准号: BB/T008008/1
• 负责人: Dingenus Meijer
• 金额: $ 74.76万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT008008%2F1
• 关键词: Molecular; mechanisms; voltage; gated; potassium

The communication between our sense organs, such as our eyes or skin, and our brain and spinal cord occurs through electrical signals that are carried by our nerves. Nerve are composed of bundles of neuronal extensions called axons. Axons conduct these signals through the regulated flux of Sodium and Potassium ions over the axonal membrane through specific channels. Many of the axons in our nerves are insulated by a fatty layer called myelin which is made and maintained by support cells called Schwann cells and oligodendrocytes. The myelin layer speeds up nerve signaling enormously, allowing us to respond rapidly and with great accuracy to any physical challenge coming our way. The way myelin speeds up signal conduction is by clustering different ion channels to high density at regularly spaced regions along the axon.The importance of this arrangement and density of ion channels becomes apparent when the integrity of the myelin layer is damaged as in multiple sclerosis or in diabetes, which alters or even block conductance. But how these ion channels are arranged and kept in specific regions is largely unknown. In this work we will examine the molecules that drive the clustering of one type of ion channel; the Kv1 class of potassium channels. Kv1 channels play important roles in normal nervous system function and mutations in the genes that encode these proteins give rise to neurological diseases such Ataxia and epilepsy. These channels are found in very high density in myelinated axons but also in other parts of the neuron. We have discovered that the specific positioning of these channels in myelinated axons is a function of two proteins; the ADAM23 receptor and its soluble binding partner LGI3. We will investigate how these molecules assemble the Kv1 channels and keep them in their fixed position. We will identify what other proteins are involved in this process and we will determine how conduction properties of myelinated axons is altered when Kv1 channels are mis-localised or removed from the axonal membrane. These important insights will further our understanding of how Kv1 channels are distributed in myelinated axons and inform us about the mechanisms that regulate Kv1 channels in other parts of the neuron to affect the basic physiological properties of the neuron and the neuronal networks they participate in, and lead to potential improvements in treating human ataxic and epileptic disorders.

我们的感觉器官（例如眼睛或皮肤）与大脑和脊髓之间的通信是通过神经携带的电信号进行的。神经由称为轴突的神经元延伸束组成。轴突通过特定通道调节轴突膜上钠离子和钾离子的通量来传导这些信号。我们神经中的许多轴突都被称为髓磷脂的脂肪层隔离，髓磷脂是由称为雪旺细胞和少突胶质细胞的支持细胞制造和维持的。髓磷脂层极大地加速了神经信号传导，使我们能够快速、准确地应对任何身体挑战。髓磷脂加速信号传导的方式是将不同的离子通道聚集在沿着轴突的规则间隔区域以高密度。当髓磷脂层的完整性受到损害（如多发性硬化症或糖尿病）时，离子通道的这种排列和密度的重要性就变得显而易见，这会改变甚至阻断电导。但这些离子通道如何排列并保持在特定区域尚不清楚。在这项工作中，我们将研究驱动一种离子通道聚集的分子； Kv1 类钾通道。 Kv1 通道在正常神经系统功能中发挥着重要作用，编码这些蛋白质的基因突变会导致共济失调和癫痫等神经系统疾病。这些通道在有髓轴突中以非常高的密度存在，而且在神经元的其他部分中也存在。我们发现这些通道在有髓轴突中的特定定位是两种蛋白质的功能； ADAM23 受体及其可溶性结合伴侣 LGI3。我们将研究这些分子如何组装 Kv1 通道并将其保持在固定位置。我们将确定哪些其他蛋白质参与此过程，并且确定当 Kv1 通道错误定位或从轴突膜移除时，有髓轴突的传导特性如何改变。这些重要的见解将进一步加深我们对 Kv1 通道如何在有髓轴突中分布的理解，并告知我们调节神经元其他部分的 Kv1 通道以影响神经元及其参与的神经元网络的基本生理特性的机制，并导致治疗人类共济失调和癫痫疾病的潜在改进。

项目成果

LGI3/2-ADAM23 interactions cluster Kv1 channels in myelinated axons to regulate refractory period.

• DOI: 10.1083/jcb.202211031
• 发表时间: 2023-04-03
• 期刊: The Journal of cell biology

Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity.

• DOI: 10.1016/j.celrep.2023.113634
• 发表时间: 2024-01-23
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Miyazaki Y;Otsuka T;Yamagata Y;Endo T;Sanbo M;Sano H;Kobayashi K;Inahashi H;Kornau HC;Schmitz D;Prüss H;Meijer D;Hirabayashi M;Fukata Y;Fukata M
• 通讯作者: Fukata M

Schwann cell precursors represent a neural crest-like state with biased multipotency.

• DOI: 10.15252/embj.2021108780
• 发表时间: 2022-09-01
• 期刊: The EMBO journal

BRN2 is a non-canonical melanoma tumor-suppressor.

• DOI: 10.1038/s41467-021-23973-5
• 发表时间: 2021-06-17
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Hamm M;Sohier P;Petit V;Raymond JH;Delmas V;Le Coz M;Gesbert F;Kenny C;Aktary Z;Pouteaux M;Rambow F;Sarasin A;Charoenchon N;Bellacosa A;Sanchez-Del-Campo L;Mosteo L;Lauss M;Meijer D;Steingrimsson E;Jönsson GB;Cornell RA;Davidson I;Goding CR;Larue L
• 通讯作者: Larue L

A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

研究基因旁系同源功能和疾病的反向遗传学和基因组学方法：肌颤搐和并列旁节。

• DOI: 10.1016/j.ajhg.2022.07.006
• 发表时间: 2022
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: Marafi,Dana;Kozar,Nina;Duan,Ruizhi;Bradley,Stephen;Yokochi,Kenji;AlMutairi,Fuad;Saadi,NebalWaill;Whalen,Sandra;Brunet,Theresa;Kotzaeridou,Urania;Choukair,Daniela;Keren,Boris;Nava,Caroline;Kato,Mitsuhiro;Arai,Hiroshi;Froukh,
• 通讯作者: Froukh,