Jacques Mbongue M. answered • 12/02/22
University Professor for Math and Science Tutoring
Na channels are the source of excitatory currents for the nervous system and muscles. They are the target for local anesthetics (LA), which have been used for local and regional anesthesia and for excitatory problems such as epilepsy and cardiac arrhythmia. The drug-binding site has been localized to the inner pore of the channel, where drugs interact mainly with phenylalanine in domain IV S6. Drug affinity is both voltage- and use-dependent. Voltage dependency results from changes in the inner pore's conformation during channel activation and opening, allowing high-energy interaction of drugs with the phenylalanine. LA drugs also reduce the gating current of Na channels, which represents the movement of charged residues in the voltage sensors. Precisely, drug binding to phenylalanine locks the domain III S4 in its outward (activated) position and slows the recovery of the domain IV S4. Although strongly affecting gating, LA drugs are almost certainly also blocked by steric occlusion of the pore.
