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CARDIOVASCULAR |
1 The Cardiac Electrophysiology Laboratory, Department of Medicine
2 The Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA
Our homology molecular model of the open/inactivated state of the Na+ channel pore predicts, based on extensive mutagenesis data, that the local anaesthetic lidocaine docks eccentrically below the selectivity filter, such that physical occlusion is incomplete. Electrostatic field calculations suggest that the drug's positively charged amine produces an electrostatic barrier to permeation. To test the effect of charge at this pore level on permeation in hNaV1.5 we replaced Phe-1759 of domain IVS6, the putative binding site for lidocaine's alkylamino end, with positively and negatively charged residues as well as the neutral cysteine and alanine. These mutations eliminated use-dependent lidocaine block with no effect on tonic/rested state block. Mutant whole cell currents were kinetically similar to wild type (WT). Single channel conductance (
) was reduced from WT in both F1759K (by 38%) and F1759R (by 18%). The negatively charged mutant F1759E increased by 14%, as expected if the charge effect were electrostatic, although F1759D was like WT. None of the charged mutations affected Na+/K+ selectivity. Calculation of difference electrostatic fields in the pore model predicted that lidocaine produced the largest positive electrostatic barrier, followed by lysine and arginine, respectively. Negatively charged glutamate and aspartate both lowered the barrier, with glutamate being more effective. Experimental data were in rank order agreement with the predicted changes in the energy profile. These results demonstrate that permeation rate is sensitive to the inner pore electrostatic field, and they are consistent with creation of an electrostatic barrier to ion permeation by lidocaine's charge.
(Received 8 February 2007;
first published online 15 March 2007)
Corresponding author H. A. Fozzard: PO Box 574, 16 Georgianna Lane, Dana, NC 28724, USA. Email: hafozzar{at}uchicago.edu
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J. Physiol. 2007 581: 423.
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