Transcompartmental reversal of single fibre hyperexcitability in juxtaparanodal Kv1.1-deficient vagus nerve axons by activation of nodal KCNQ channels.
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 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.
J. L. Noebels: Department of Neurology, Baylor College of Medicine, One Baylor Plaza, NB220, Houston, TX 77030, USA.  jnoebels@bcm.edu.
Edward
E
Glasscock
Jing
J
Qian
Matthew J
MJ
Kole
Jeffrey L
JL
Noebels
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism*; D051662:Kv1.1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D014630:Vagus Nerve / Q000166:cytology* / Q000502:physiology*
D000911:Antibodies, Monoclonal; D051656:KCNQ Potassium Channels; D051662:Kv1.1 Potassium Channel; D004247:DNA