Block of sodium channels in planar lipid bilayers by guanidium toxins and calcium. Are the mechanisms of voltage dependence the same?
The block of single, batrachotoxin-activated sodium channels by saxitoxin (STX), tetrodotoxin (TTX), and Ca2+ has been investigated in planar bilayers. All three substances block in a voltage-dependent manner with hyperpolarizing potentials favoring block. Extracellular Ca2+ competitively inhibits binding of STX and relieves STX block. Trimethyloxonium, a carboxyl-methylating agent, eliminates block by STX and TTX and dramatically reduces block by Ca2+. These results suggest that STX, TTX, and Ca2+ compete for a negative site on the outside of the channel. The voltage dependence of block by STX (divalent cation) and TTX (monovalent) was similar (40 mV/e-fold), suggesting that voltage dependence is due to a conformational change in the channel rather than to the toxins entering the membrane electric field to block. A physical model, with an external binding site for toxins and Ca2+ and another site deeper within the electric field (associated with the "selectivity filter") that is accessible to Ca2+ but not toxins, predicts voltage-dependence Ca2+ block without invoking the conformational change needed to explain the voltage dependence of block by TTX and STX.
D000818:Animals; D001496:Batrachotoxins / Q000494:pharmacology*; D001921:Brain / Q000502:physiology; D002118:Calcium / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008051:Lipid Bilayers; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D010714:Phosphatidylethanolamines; D051381:Rats; D012530:Saxitoxin / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels
D001496:Batrachotoxins; D007473:Ion Channels; D008051:Lipid Bilayers; D008565:Membrane Proteins; D010714:Phosphatidylethanolamines; D015222:Sodium Channels; D012530:Saxitoxin; D012964:Sodium; D002118:Calcium