Enhanced K + Currents Contribute to Saltatory Conduction Impairment in Mechanically Demyelinated Aα-Fibers of Rats

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Abstract
Saltatory conduction of action potentials (APs) through nodes of Ranvier (NRs) is essential for the rapid and precise conduction of neuronal signals along heavily myelinated axons. However, in demyelinating diseases, saltatory conduction becomes impaired, leading to sensory and motor dysfunctions. At NRs of normal heavily myelinated nerves, APs are depolarized by voltage-gated Na + channels and repolarized mainly by K + currents flowing through two-pore-domain K + channels (K2P). Interestingly, although voltage-gated K + channels are present at and around NRs, they exhibit only limited activity and contribute minimally to nodal excitability and AP repolarization under physiological conditions. Here, we show that voltage-activated K + currents are significantly increased at NRs of motor Aα-fibers in the ventral roots of male and female rat lumbar spinal nerves following mechanical compression to induce acute demyelination. The increase in K + currents is associated with profound changes in intrinsic electrophysiological properties that reflect hypoexcitability at NRs and impairments of saltatory conduction. Voltage-gated K + channel blockers significantly reduce K + currents, restore excitability, and improve saltatory conduction at NRs of demyelinated Aα-fibers. Pharmacological profiling identifies Kv1.1 and Kv1.2 as the predominant voltage-gated K + channel subtypes contributing to the functional abnormality at NRs of demyelinated Aα-fibers. Collectively, our findings uncover a mechanistic link between abnormally enhanced K + currents via Kv1.1 and Kv1.2 channels and the impairment of saltatory conduction at NRs of demyelinated Aα-fibers, providing new insights into potential interventions for demyelinating disorders.
Funding Information
  • HHS | NIH | National Institute of Dental and Craniofacial Research (DE018661)
  • HHS | NIH | National Institute of Dental and Craniofacial Research (DE023090)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS109059)

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