SkM2, a Na+ channel cDNA clone from denervated skeletal muscle, encodes a tetrodotoxin-insensitive Na+ channel.

Approximately one third of the Na+ channels expressed in denervated or developing skeletal muscle are tetrodotoxin (TTX) insensitive, with a Kd for channel blockade of approximately 1 microM, similar to that found for cardiac Na+ channels. We have recently reported the cloning of a putative Na+ channel subtype that is characteristic of denervated and developing skeletal muscle (SkM2), the deduced amino acid sequence of which is identical to that of a Na+ channel cDNA isolated from heart. We have now examined the functional properties of SkM2 Na+ channels after expression in Xenopus oocytes. We found that the efficiency of expression of constructs containing the SkM2 clone was strongly dependent on the amount of 5'-untranslated region (5'UTR) included. Constructs containing a 206-nucleotide 5'UTR were expressed poorly, whereas constructs from which most of the 5'UTR was removed were expressed well. The channels showed rapid voltage-dependent activation and inactivation. In addition, SkM2 Na+ channels were insensitive to low concentrations of TTX but were ultimately blocked by this toxin, with a Kd of 1.9 microM. The TTX block exhibited use dependence. Finally, SkM2 Na+ channels were not blocked by 100 nM mu-conotoxin, which blocks Na+ channels in innervated skeletal muscle in the low nanomolar concentration range. These data indicate that SkM2 Na+ channels are the TTX-insensitive Na+ channels found in denervated or developing skeletal muscle and are identical to the TTX-insensitive Na+ channels from heart.