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Mar. Drugs 2013, 11(6), 2140-2153; doi:10.3390/md11062140
Article

Tetrodotoxin Blockade on Canine Cardiac L-Type Ca2+ Channels Depends on pH and Redox Potential

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1 Department of Physiology, University of Debrecen, P.O. Box 22, H-4012 Debrecen, Hungary 2 Clinical Research Center and Thrombosis Haemostasis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, P.O. Box 40, H-4012 Debrecen, Hungary 3 Department of Dental Physiology and Pharmacology, Medical and Health Science Center, University of Debrecen, P.O. Box 22, H-4012 Debrecen, Hungary
* Author to whom correspondence should be addressed.
Received: 17 February 2013 / Revised: 22 April 2013 / Accepted: 20 May 2013 / Published: 14 June 2013
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Abstract

Tetrodotoxin (TTX) is believed to be one of the most selective inhibitors of voltage-gated fast Na+ channels in excitable tissues. Recently, however, TTX has been shown to block L-type Ca2+ current (ICa) in canine cardiac cells. In the present study, the TTX-sensitivity of ICa was studied in isolated canine ventricular myocytes as a function of (1) channel phosphorylation, (2) extracellular pH and (3) the redox potential of the bathing medium using the whole cell voltage clamp technique. Fifty-five micromoles of TTX (IC50 value obtained under physiological conditions) caused 60% ± 2% inhibition of ICa in acidic (pH = 6.4), while only a 26% ± 2% block in alkaline (pH = 8.4) milieu. Similarly, the same concentration of TTX induced 62% ± 6% suppression of ICa in a reductant milieu (containing glutathione + ascorbic acid + dithiothreitol, 1 mM each), in contrast to the 31% ± 3% blockade obtained in the presence of a strong oxidant (100 μM H2O2). Phosphorylation of the channel protein (induced by 3 μM forskolin) failed to modify the inhibiting potency of TTX; an IC50 value of 50 ± 4 μM was found in forskolin. The results are in a good accordance with the predictions of our model, indicating that TTX binds, in fact, to the selectivity filter of cardiac L-type Ca channels.
Keywords: tetrodotoxin; calcium current; dog heart; pH dependence; redox potential tetrodotoxin; calcium current; dog heart; pH dependence; redox potential
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Hegyi, B.; Komáromi, I.; Kistamás, K.; Ruzsnavszky, F.; Váczi, K.; Horváth, B.; Magyar, J.; Bányász, T.; Nánási, P.P.; Szentandrássy, N. Tetrodotoxin Blockade on Canine Cardiac L-Type Ca2+ Channels Depends on pH and Redox Potential. Mar. Drugs 2013, 11, 2140-2153.

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