| Summary: | Spinal cord injury (SCI) causes neuronal death, demyelination of surviving axons, and altered ion channel functioning, resulting in impaired axonal conduction. The large-conductance, voltage and Ca2+-activated K+ (BK or Maxi K+) channels contribute to the repolarization phase of action potentials. Therefore, they may play a significant role in regulating axonal conduction in SCI. In this paper, using combined electrophysiological and molecular approaches, we tested the hypothesis that the deficit in axonal conduction in chronic SCI is partially due to the activation of axonal BK channels. BK channels were found to be expressed in spinal cord white matter axons. These channels are not sensitive to BK channel blocker iberiotoxin in uninjured cords, likely reflecting their juxtaparanodal localization. After chronic injury, BK channels were exposed due to axonal demyelination at the injured site and their activation was found to depend on calcium influx, likely through N-type voltage-dependent calcium channels. Activation of BK channels introduced a reduction in the size of the compound action potentials (CAPs) and in axonal response to high frequency stimulation (HFS). Administration of BK channel blocker iberiotoxin significantly enhanced axonal conduction in the injured cords. Thus, pharmacological targeting of axonal BK channels may provide a therapeutic strategy for the treatment of chronic SCI, by restoring conduction to the remaining functional axons.
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