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Atomic determinants of state‐dependent block of sodium channels by charged local anesthetics and benzocaine
Author(s) -
Tikhonov Denis B.,
Bruhova Iva,
Zhorov Boris S.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.10.035
Subject(s) - benzocaine , chemistry , cationic polymerization , ammonium , biophysics , sodium , biology , organic chemistry , immunology
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.