| | Atomic determinants of state-dependent block of sodium channels by charged local anesthetics and benzocaineEdited by Maurice Montal Received 4 September 2006; received in revised form 11 October 2006; accepted 12 October 2006. published online 24 October 2006. Abstract Molecular modeling predicts that a local anesthetic (LA) lidocaine binds to the resting and open Nav1.5 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. Abbreviations: 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 Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ont., Canada L8N 3Z5  Corresponding author. Fax: +1 905 522 9033.
PII: S0014-5793(06)01251-8 doi:10.1016/j.febslet.2006.10.035 © 2006 Federation of European Biochemical Societies | |
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ABSTRACT
