Rapid protein kinase C-dependent reduction of rat skeletal muscle voltage-gated sodium channels by ciliary neurotrophic factor.
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.
Talon
S
S
UMR 6204 CNRS, Faculté des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France. soptalon@yahoo.com
Giroux-Metges
M-A
MA
Pennec
J-P
JP
Guillet
C
C
Gascan
H
H
Gioux
M
M
D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000502:physiology*
D020934:Ciliary Neurotrophic Factor; D015222:Sodium Channels; D012964:Sodium; D011493:Protein Kinase C