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Research Papers
Irreversible Block of Cardiac Mutant Na+ Channels by Batrachotoxin
Sho-Ya Wang, Denis B. Tikhonov, Jane Mitchell, Boris Zhorov and Ging Kuo Wang
volume 1 | issue 3
May/June 2007Pages: 179 - 188
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Batrachotoxin (BTX) not only keeps the voltage-gated Na+ channel open persistently but also reduces its single-channel conductance. Although a BTX receptor has been delimited within the inner cavity of Na+ channels, how Na+ ions flow through the BTX-bound permeation pathway remains unclear. In this report we tested a hypothesis that Na+ ions traverse a narrow gap between bound BTX and residue N927 at D2S6 of cardiac hNav1.5 Na+ channels. We found that BTX at 5 uM indeed elicited a strong block of hNav1.5-N927K currents (~70%) after 1000 repetitive pulses (+50 mV/20 ms at 2 Hz) without any effects on Na+ channel gating. Once occurred, this unique use-dependent block of hNav1.5-N927K Na+ channels recovered little at holding potential (−140 mV), demonstrating that BTX block is irreversible under our experimental conditions. Such an irreversible effect likewise developed in fast inactivation-deficient hNav1.5-N927K Na+ channels albeit with a faster on-rate; ~90% of peak Na+ currents were abolished by BTX after 200 repetitive pulses (+50 mV/20 ms). This use-dependent block of fast inactivation-deficient hNav1.5-N927K Na+ channels by BTX was duration dependent. The longer the pulse duration the larger the block developed. Among N927K/W/R/H/D/S/Q/G/E substitutions in fast inactivation-deficient hNav1.5 Na+ channels, only N927K/R Na+ currents were highly sensitive to BTX block. We conclude that (a) BTX binds within the inner cavity and partly occludes the permeation pathway and (b) residue hNav1.5-N927 is critical for ion permeation between bound BTX and D2S6, probably because the side-chain of N927 helps coordinate permeating Na+ ions.
Authors
Sho-Ya Wang
Department of Biology, State University of New York at Albany, Albany, NY
Denis B. Tikhonov
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
Jane Mitchell
Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Boris Zhorov
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
Ging Kuo Wang
Department of Anesthesia, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.