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Tetrodotoxin Blockade on Canine Cardiac L-Type Ca2+ Channels Depends on pH and Redox Potential
Department of Physiology, University of Debrecen, P.O. Box 22, H-4012 Debrecen, Hungary
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
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; in revised form: 22 April 2013 / Accepted: 20 May 2013 / Published: 14 June 2013
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
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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.
Hegyi B, Komáromi I, Kistamás K, Ruzsnavszky F, Váczi K, Horváth B, Magyar J, Bányász T, Nánási PP, Szentandrássy N. Tetrodotoxin Blockade on Canine Cardiac L-Type Ca2+ Channels Depends on pH and Redox Potential. Marine Drugs. 2013; 11(6):2140-2153.
Hegyi, Bence; Komáromi, István; Kistamás, Kornél; Ruzsnavszky, Ferenc; Váczi, Krisztina; Horváth, Balázs; Magyar, János; Bányász, Tamás; Nánási, Péter P.; Szentandrássy, Norbert. 2013. "Tetrodotoxin Blockade on Canine Cardiac L-Type Ca2+ Channels Depends on pH and Redox Potential." Mar. Drugs 11, no. 6: 2140-2153.