Mechanism of Local Anesthetic Drug Action on Voltage-Gated Sodium Channels

Abstract

Local anesthetic drugs interfere with excitation and conduction by action potentials in the nervous system and in the heart by blockade of the voltage-gated Na channel. Drug affinity varies with gating state of the channel. The drugs show low affinity at slow excitation rates, but high affinity when the channels are opened and inactivated during action potentials at high frequency, as they are during pain or during a cardiac arrhythmia. The drugs are thought to access their binding site in the inner pore by passage through the membrane and entry through the inner pore vestibule. There have been three major developments in the last decade that greatly increase our understanding of their mechanism of action. Firstly, amino acid residues critical to drug binding have been located by mutagenesis, and it is possible to develop a molecular model of the drug binding site. Secondly, a path for drug access directly from the outside has been characterized in the cardiac isoform of the channel. Thirdly, the hypothesis that high affinity binding stabilizes the fast inactivated conformation of the channel has been challenged. Rather, the drug may stabilize a slow inactivated state and immobilize the voltage sensor in domain III in its activated outward position. The combination of mutational study of the cloned Na channels and patch clamp offers the opportunity to understand the detailed molecular mechanism of drug action and to resolve drug structure-function.

Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel

“…Fenestration size is modulated by S6 bending, which we have proposed may be associated with a collapse into an inactivated state. These observations suggest that the binding of drugs at this crucial site could modulate conversion to a slowinactivated state, as suggested experimentally (28,31,32,46). These simulations have therefore proven to be important for exploring the roles of protein flexibility in ion conduction mechanisms and have given us clues as to the molecular-level processes that underscore inactivation and drug inhibition of Na v channels.…”

“…It has been suggested that drugs can enter the cavity (48) and physically block the channel (49), or bind at the level of the opening via π-π stacking of aromatics (47) and inhibit the current by favoring a nonconductive inactivated state (46). Moreover, it is known that slow inactivation is affected by local anesthetics or antiepileptics drugs (30)(31)(32) and by the mutation of the same Phe involved in drug binding (28). Evidence suggests that drug binding affinity varies depending on the conducting state of the channels (46), corroborating our own observations that accessibility of both the Phe and cavity openings are codependent and correlated with changes in the S6 helix and gate collapse, suggesting a transition to the inactivated state.…”

“…Bacterial channels display slow inactivation reminiscent of C-type inactivation in K v channels (27), involving its PD (28,29), and is known to be modulated by local anesthetics (8). Interestingly, there is recent evidence that mammalian channels are also affected by this process (30)(31)(32), despite a historical focus on fast inactivation (33). Our multimicrosecond simulations reveal conformational fluctuations in common with proposed inactivated crystal structures (34), which allow us to begin to describe the molecular mechanisms of inactivation and its relation to Na v drug inhibition.…”

The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides

“…1). Second, both LAs and DCJW are believed to bind preferably to slow-inactivated channels (10,16,25). In the case of LAs, the preference is likely due to the lack of electrostatic repulsion between the ligand charged group and the cationdeficient outer pore (13).…”

“…SCBIs are believed to bind to and trap sodium channels in non-conducting slow inactivated states (9), the mechanism similar to that proposed for local anesthetics (LAs) (1,10). Molecular interactions of LAs with mammalian sodium channels have been intensively studied (11,12).…”