Transcompartmental reversal of single fibre hyperexcitability in juxtaparanodal Kv1.1-deficient vagus nerve axons by activation of nodal KCNQ channels
Transcompartmental reversal of single fibre hyperexcitability in juxtaparanodal Kv1.1-deficient vagus nerve axons by activation of nodal KCNQ channels
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DOI：
10.1113/jphysiol.2012.235606
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发表时间：
2012-08-01
影响因子：
5.5
通讯作者：
Noebels, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Glasscock, Edward;Qian, Jing;Noebels, Jeffrey L.
Kv1.1通道聚集在迷走神经中的有髓轴突的前动脉，迷走神经是心脏副交感神经支配的主要管道。缺乏这些通道的kcna 1基因敲除小鼠表现出神经心脏功能障碍，表现为阿托品敏感性房室传导阻滞和心动过缓，最终可能导致猝死。为了评估Kv1.1通道的缺失是否会改变神经内的产电特性，我们比较了年轻成年Kcna 1-nullmice和年龄匹配的野生型同窝对照小鼠的离体颈迷走神经的单个有髓鞘A-和A-δ-轴突的内在兴奋性。虽然动作电位的形状和相对不应期的基因型之间的变化不大，Kv1.1缺陷的大型有髓鞘的A-轴突表现出5倍的敏感性增加4-氨基吡啶（4-AP）诱导的自发性异位放电。由于结旁Kv 1通道和结KCNQ钾通道的复极化电流都起到抑制重复活动的作用，我们研究了增加结KCNQ激活是否可以补偿Kv1.1损失并逆转Kv1.1缺陷A-轴突的自发性超兴奋性。应用选择性KCNQ开放剂氟吡汀提高了A-轴突放电阈值，同时深刻抑制4-AP诱导的自发放电，表明两个隔室之间的功能协同作用。我们的结论是，arctaparanodal Kv1.1-缺陷导致内在的过度兴奋，在大的有髓轴突迷走神经，这可能有助于自主神经功能障碍的Kcna 1-null小鼠，KCNQ开放揭示了跨室协同作用Kv 1和KCNQ通道调节轴突兴奋性。
Kv1.1 channels cluster at juxtaparanodes of myelinated axons in the vagus nerve, the primary conduit for parasympathetic innervation of the heart. Kcna1-null mice lacking these channels exhibit neurocardiac dysfunction manifested by atropine-sensitive atrioventricular conduction blocks and bradycardia that may culminate in sudden death. To evaluate whether loss of Kv1.1 channels alters electrogenic properties within the nerve, we compared the intrinsic excitability of single myelinated A- and A delta-axons from excised cervical vagus nerves of young adult Kcna1-nullmice andage-matched, wild-type littermate controls. Although action potential shapes and relative refractory periods varied little between genotypes, Kv1.1-deficient large myelinated A-axons showed a fivefold increase in susceptibility to 4-aminopyridine (4-AP)-induced spontaneous ectopic firing. Since the repolarizing currents of juxtaparanodal Kv1 channels and nodal KCNQ potassium channels both act to dampen repetitive activity, we examined whether augmenting nodal KCNQ activation could compensate for Kv1.1 loss and reverse the spontaneous hyperexcitability in Kv1.1-deficient A-axons. Application of the selective KCNQ opener flupirtine raised A-axon firing threshold while profoundly suppressing 4-AP-induced spontaneous firing, demonstrating a functional synergy between the two compartments. We conclude that juxtaparanodal Kv1.1-deficiency causes intrinsic hyperexcitability in large myelinated axons in vagus nerve which could contribute to autonomic dysfunction in Kcna1-null mice, and that KCNQ openers reveal a transcompartmental synergy between Kv1 and KCNQ channels in regulating axonal excitability.