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FEBS Lett. 2006 Nov 13;580(26):6027-32. Epub 2006 Oct 24.

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

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1
Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ont., Canada L8N 3Z5.

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.

PMID:
17070808
DOI:
10.1016/j.febslet.2006.10.035
[Indexed for MEDLINE]
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