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Low concentrations of tetrodotoxin interact with tetrodotoxin‐resistant voltage‐gated sodium channels
Author(s) -
Farmer C E,
Smith K J,
Docherty R J
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.235
Subject(s) - tetrodotoxin , sodium channel , biophysics , chemistry , extracellular , dorsal root ganglion , patch clamp , voltage clamp , voltage dependent calcium channel , electrophysiology , membrane potential , sodium , calcium , biochemistry , neuroscience , anatomy , biology , receptor , dorsum , organic chemistry
Background and purpose: Tetrodotoxin (TTX) is used to distinguish between two classes of voltage‐gated sodium channel (VGSC)—TTX sensitive (TTXS) and TTX resistant (TTXR). The resistance of TTXR VGSCs is thought to result from a low binding affinity of TTX, although at high TTX concentrations channel block does occur. Here, we show that, at concentrations below those which produce block, TTX can bind to TTXR VGSCs. Experimental approach: Whole‐cell voltage clamp recordings were made from dissociated rat dorsal root ganglion neurones that expressed both TTXS and TTXR sodium currents. Voltage‐gated calcium currents were blocked by 10 μ M extracellular lanthanum chloride. TTXS, but not TTXR, current was suppressed by using a holding potential of −50 mV, and the effect of TTX on the isolated TTXR current was explored. Key results: Extracellular application of 0.5 μ M TTX produced a 40% increase in TTXR current amplitude, a negative shift in the voltage‐dependence of current activation (approximately −8 mV) and inactivation (approximately −10 mV) and increased rates of current activation and inactivation. The effect of TTX on current amplitude was dose‐dependent (EC 50 =364 n M ). Removal of lanthanum prevented the effect of TTX on TTXR current amplitude, whereas reducing extracellular calcium did not. Conclusions and implications: The findings are consistent with an interpretation that TTX relieves a tonic block of the TTXR VGSC by lanthanum. We conclude that TTX binds to the TTXR VGSC at low concentrations, without blocking it. This appears to be the first demonstration of a clear distinction between binding affinity and blocking potency of a channel‐blocking agent. British Journal of Pharmacology (2008) 155 , 34–43; doi: 10.1038/bjp.2008.235 ; published online 16 June 2008