Atomic determinants of state-dependent block of sodium channels by charged local anesthetics and benzocaine |
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Authors: | Tikhonov Denis B Bruhova Iva Zhorov Boris S |
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Affiliation: | Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ont., Canada L8N 3Z5. |
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Abstract: | Molecular modeling predicts that a local anesthetic (LA) lidocaine binds to the resting and open Na(v)1.5 in different modes, interacting with LA-sensing residues known from experiments. Besides the major pathway via the open activation gate, LAs can reach the inner pore via a "sidewalk" between D3S6, D4S6, and D3P. The ammonium group of a cationic LA binds in the focus of the pore-helices macrodipoles, which also stabilize a Na(+) ion chelated by two benzocaine molecules. The LA's cationic group and a Na(+) ion in the selectivity filter repel each other suggesting that the Na(+) depletion upon slow inactivation would stabilize a LA, while a LA would stabilize slow-inactivated states. |
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Keywords: | LA, local anesthetic MC, Monte Carlo DEKA, the circular locus of residues Asp, Glu, Lys, and Ala from P-loops in domains D1-D4, respectively, which form the Na+ channel selectivity filter D1S6-D4S6, the inner helices in domains D1-D4, respectively D3P, the pore helix in domain 3 |
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