Fenestrations control resting-state block of a voltage-gated sodium channel.

ABSTRACT: Potency of drug action is usually determined by binding to a specific receptor site on target proteins. In contrast to this conventional paradigm, we show here that potency of local anesthetics (LAs) and antiarrhythmic drugs (AADs) that block sodium channels is controlled by fenestrations that allow drug access to the receptor site directly from the membrane phase. Voltage-gated sodium channels initiate action potentials in nerve and cardiac muscle, where their hyperactivity causes pain and cardiac arrhythmia, respectively. LAs and AADs selectively block sodium channels in rapidly firing nerve and muscle cells to relieve these conditions. The structure of the ancestral bacterial sodium channel Na_VAb, which is also blocked by LAs and AADs, revealed fenestrations connecting the li

SUBMITTER: Gamal El-Din TM 

PROVIDER: S-EPMC6304959 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature