HCN Channel-mediated neuromodulation can control action potential velocity and fidelity in central axons
HCN Channel-mediated neuromodulation can control action potential velocity and fidelity in central axons
复制标题
DOI：
10.7554/elife.42766
复制
发表时间：
2019-09-09
期刊：
影响因子：
7.7
通讯作者：
Hallermann, Stefan
中科院分区：
文献类型：
--
作者：
Byczkowicz, Niklas;Eshra, Abdelmoneim;Hallermann, Stefan
超极化激活的环核苷酸门控（HCN）通道控制心脏和大脑中的电节律和兴奋性，但HCN通道在轴突亚细胞水平上的功能仍然知之甚少。在这里，我们表明，动作电位传导速度在有髓和无髓的中央轴突可以双向调制的HCN通道阻滞剂，环磷酸腺苷（cAMP），和神经调质。从小鼠小脑苔藓纤维扣的记录表明，HCN通道，确保可靠的高频发射和强烈调制cAMP（EC 50 40 μ M，估计内源性cAMP浓度13 μ M）。此外，免疫金电子显微镜显示HCN 2作为小脑苔藓纤维的主要亚基。计算模型表明，HCN 2通道主要通过改变静息膜电位来控制传导速度，并与显著的代谢成本相关。这些结果表明，cAMP-HCN通路为神经调节剂提供了微调大脑轴突能量消耗和时间延迟的机会。
Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical rhythmicity and excitability in the heart and brain, but the function of HCN channels at the subcellular level in axons remains poorly understood. Here, we show that the action potential conduction velocity in both myelinated and unmyelinated central axons can be bidirectionally modulated by a HCN channel blocker, cyclic adenosine monophosphate (cAMP), and neuromodulators. Recordings from mouse cerebellar mossy fiber boutons show that HCN channels ensure reliable high-frequency firing and are strongly modulated by cAMP (EC50 40 mu M; estimated endogenous cAMP concentration 13 mu M). In addition, immunogold-electron microscopy revealed HCN2 as the dominating subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 channels control conduction velocity primarily by altering the resting membrane potential and are associated with significant metabolic costs. These results suggest that the cAMP-HCN pathway provides neuromodulators with an opportunity to finely tune energy consumption and temporal delays across axons in the brain.