Atomic determinants of state-dependent block of sodium channels by charged local anesthetics and benzocaine.
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.
Tikhonov
Denis B
DB
Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ont., Canada L8N 3Z5.
Bruhova
Iva
I
Zhorov
Boris S
BS
D000779:Anesthetics, Local / Q000737:chemistry / Q000493:pharmacokinetics*; D001566:Benzocaine / Q000737:chemistry / Q000493:pharmacokinetics*; D001665:Binding Sites; D006801:Humans; D008012:Lidocaine / Q000737:chemistry / Q000493:pharmacokinetics*; D008958:Models, Molecular; D015394:Molecular Structure; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011487:Protein Conformation; D012964:Sodium / Q000737:chemistry; D015222:Sodium Channels / Q000737:chemistry* / Q000378:metabolism*
D000779:Anesthetics, Local; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D008012:Lidocaine; D012964:Sodium; D001566:Benzocaine