Transcompartmental reversal of single fibre hyperexcitability in juxtaparanodal Kv1.1‐deficient vagus nerve axons by activation of nodal KCNQ channels

Key points • Voltage‐gated Kv1.1 potassium channels cluster at juxtaparanodes of myelinated axons in the vagus nerve, which provides parasympathetic innervation to the heart. • Kcna1 knockout mice lacking Kv1.1 channels exhibit frequent atrioventricular cardiac conduction blocks that are abolished by atropine, suggestive of a vagal mechanism. • Electrophysiological analysis of single myelinated axons from wild‐type and Kv1.1‐deficient mouse vagus nerves revealed that the absence of Kv1.1 channels rendered large myelinated vagal axons far more susceptible to spontaneous ectopic firing in the presence of 4‐aminopyridine. • KCNQ2 potassium channels are present within vagal nodes of Ranvier and their activation with flupirtine rescued single axon hyperexcitability mediated by juxtaparanodal Kv1.1‐deficiency. • These results demonstrate a functional synergy between nodal and extranodal K+ channels and implicate KCNQ channels as potential targets for Kv1‐related peripheral nerve hyperexcitability. 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 Aδ‐axons from excised cervical vagus nerves of young adult Kcna1‐null mice and age‐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