Atomic determinants of state-dependent block of sodium channels by charged local anesthetics and benzocaine

Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ont., Canada L8N 3Z5.
FEBS Letters (Impact Factor: 3.34). 12/2006; 580(26):6027-32. DOI: 10.1016/j.febslet.2006.10.035
Source: PubMed

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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