Dose-dependent modulation of the cardiac sodium channel by sea anemone toxin ATXII.
The effects of sea anemone toxin ATXII on single sodium channels were studied in cell-attached patches on rabbit ventricular myocytes at 20-22 degrees C. Exposure of patches to 1,000 nM ATXII induced long-lasting bursts of openings, which were more dramatically different from control at -20 mV than at -50 mV. Mean open duration, which had a biphasic dependence on voltage in control patches, was monotonically dependent on voltage in toxin-exposed patches, being 3.5 times longer than control at -20 mV and 4.5 times longer at -10 mV. Multiple mean open durations were detected at depolarized potentials. To test whether the multiple mean open durations resulted from a mixture of modified and unmodified openings, histograms of late openings (when unmodified channels would be inactivated) were constructed. Because in most cases these fit a single exponential with a mean open duration like that of modified channels, we conclude that voltage-dependent toxin unbinding produced a mixed population of unmodified and modified openings. Consistent with this hypothesis, lower concentrations of toxin most often produced open-duration histograms best fit with two exponentials. Ensembles revealed complex decay kinetics, which could be interpreted within the context of the toxin-induced increase in mean open duration and burst duration and the summation of modified and unmodified events. Analysis of the numbers of early versus late events at -20 mV for patches exposed to 20 nM, 100 nM, and 1,000 nM ATXII predicted the ED50 for ATXII block to be 285 nM at this potential. Using a five-state Markovian model, the action of ATXII could be explained as a reduction of the open-to-inactivated rate constant without effect on inactivation from closed states or other rate transitions.
Cardiac Electrophysiology Laboratories, University of Chicago, Ill.
N
N
el-Sherif
H A
HA
Fozzard
D A
DA
Hanck
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D003064:Cnidarian Venoms / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D009206:Myocardium / Q000378:metabolism*; D009994:Osmolar Concentration; D011817:Rabbits; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology
D002316:Cardiotonic Agents; D003064:Cnidarian Venoms; D015222:Sodium Channels; C028800:toxin II (Anemonia sulcata)