Rapid protein kinase C-dependent reduction of rat skeletal muscle voltage-gated sodium channels by ciliary neurotrophic factor

J Physiol. 2005 Jun 15;565(Pt 3):827-41. doi: 10.1113/jphysiol.2005.084681. Epub 2005 Apr 14.

Abstract

The ciliary neurotrophic factor (CNTF), known to exert long-term myotrophic effects, has not yet been shown to induce a rapid biological response in skeletal muscles. The present in vitro study gives rise to the possibility that CNTF could affect the sodium channel activity implied in the triggering of muscle fibre contraction. Therefore, we investigated the effects of an external CNTF application on macroscopic sodium current (I(Na)) in rat native fast-twitch skeletal muscle (flexor digitorum brevis, FDB) by using a cell-attached patch-clamp technique. The I(Na) peak amplitude measured at a depolarizing pulse from -100 to -10 mV is rapidly reduced in a time- and dose-dependent manner by CNTF (0.01-20 ng ml(-1)). The maximal decrease is 25% after 10 min incubation in 2 ng ml(-1) CNTF. There was no alteration in activation or inactivation kinetics, or in activation curves constructed from current-voltage relationships in the presence of CNTF. In contrast, the relative I(Na) inhibition induced by CNTF is accompanied by a hyperpolarizing shift in the midpoint of the inactivation curves: -6 and -10 mV for the steady-state fast and slow inactivation, respectively. Furthermore, CNTF induces a 5 mV hyperpolarization of the resting membrane potential of the fibres. The effects of CNTF are similar to those of 1-oleoyl-2-acetyl-sn-glycerol (OAG), a protein kinase C (PKC) activator, when no effect is observed in the presence of chelerythrine, a PKC inhibitor. These results suggest that, in skeletal muscle, CNTF can rapidly decrease sodium currents by altering inactivation gating, probably through an intracellular PKC-dependent mechanism that could lead to decreased membrane excitability. The present study contributes to a better understanding of the physiological role of endogenous CNTF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ciliary Neurotrophic Factor / pharmacology*
  • Ciliary Neurotrophic Factor / physiology
  • Dose-Response Relationship, Drug
  • In Vitro Techniques
  • Ion Channel Gating / drug effects*
  • Ion Channel Gating / physiology
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Muscle, Skeletal / physiology*
  • Patch-Clamp Techniques
  • Protein Kinase C / metabolism*
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sodium / metabolism
  • Sodium Channels / physiology*

Substances

  • Ciliary Neurotrophic Factor
  • Sodium Channels
  • Sodium
  • Protein Kinase C