Centre for Discovery Brain Sciences, University of Edinburgh , Edinburgh. UK.
Department of Molecular Cell Biology and Molecular Neurobiology, Weizmann Institute of Science , Rehovot, Israel.
J Cell Biol. 2023 Apr 3;222(4). doi: 10.1083/jcb.202211031. Epub 2023 Feb 24.
Along myelinated axons, Shaker-type potassium channels (Kv1) accumulate at high density in the juxtaparanodal region, directly adjacent to the paranodal axon-glia junctions that flank the nodes of Ranvier. However, the mechanisms that control the clustering of Kv1 channels, as well as their function at this site, are still poorly understood. Here we demonstrate that axonal ADAM23 is essential for both the accumulation and stability of juxtaparanodal Kv1 complexes. The function of ADAM23 is critically dependent on its interaction with its extracellular ligands LGI2 and LGI3. Furthermore, we demonstrate that juxtaparanodal Kv1 complexes affect the refractory period, thus enabling high-frequency burst firing of action potentials. Our findings not only reveal a previously unknown molecular pathway that regulates Kv1 channel clustering, but they also demonstrate that the juxtaparanodal Kv1 channels that are concealed below the myelin sheath, play a significant role in modifying axonal physiology.
沿有髓轴突，Shaker 型钾通道（Kv1）在靠近结旁区的位置高度聚集，此处紧邻连接郎飞结的轴突-神经胶质连接部。然而，控制 Kv1 通道聚集的机制，以及它们在该部位的功能，仍然知之甚少。在这里，我们证明了轴突 ADAM23 对于结旁区 Kv1 复合物的积累和稳定性都是必需的。ADAM23 的功能严重依赖于其与细胞外配体 LGI2 和 LGI3 的相互作用。此外，我们证明了结旁区 Kv1 复合物影响不应期，从而使动作电位的高频爆发式放电成为可能。我们的发现不仅揭示了一个以前未知的调节 Kv1 通道聚集的分子途径，而且还表明隐藏在髓鞘下的结旁 Kv1 通道在改变轴突生理学方面起着重要作用。
