Tetrodotoxin-sensitive and tetrodotoxin-resistant Na+ channels differ in their sensitivity to Cd2+ and Zn2+.
The sensitivity of Na+ channels to inhibition by Cd2+ and Zn2+ was studied in 22Na+ uptake experiments after stabilization of an open conformation of the Na+ channels with different neurotoxins and in voltage clamp experiments. Six different cell types of neuronal, cardiac or skeletal muscle origin were surveyed. Three cell types possess Na+ channels that are highly sensitive to tetrodotoxin (TTX) (Kd = 1-5 nM) and three possess Na+ channels that are resistant to TTX (Kd = 0.3-1 microM). The 22Na+ uptake experiments using veratridine or batrachotoxin to activate Na+ channels indicated that TTX-resistant Na+ channels are more sensitive to the inhibitory action of Cd2+ (IC50(Cd2+) = 0.2 mM) and of Zn2+ (IC50(Zn2+) = 50 microM) than TTX-sensitive Na+ channels (IC50(Cd2+) = 5 mM, IC50(Zn2+) = 2 mM). Electrophysiological experiments showed that high concentrations of Cd2+ (IC50 = 2 mM) are necessary to inhibit both TTX-sensitive and TTX-insensitive Na+ channels when the channels are activated by voltage steps. The results suggest that Cd2+ acts competitively with veratridine or batrachotoxin and that the difference in the effects of Cd2+ and Zn2+ on 22Na+ fluxes in TTX-sensitive and TTX-resistant cells is related to differences at the site of action of alkaloid neurotoxins.
Frelin
C
C
Cognard
C
C
Vigne
P
P
Lazdunski
M
M
D000818:Animals; D001496:Batrachotoxins / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology*; D002478:Cells, Cultured; D007473:Ion Channels / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009132:Muscles / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology*; D014701:Veratridine / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*
D001496:Batrachotoxins; D007473:Ion Channels; D002104:Cadmium; D013779:Tetrodotoxin; D010042:Ouabain; D014701:Veratridine; D012964:Sodium; D015032:Zinc