title: Mechanism of Inactivation in Voltage-Gated Na(+) Channels.
abstract: Voltage-gated Na(+) channels (VGSCs) initiate action potentials thereby giving rise to rapid transmission of electrical signals along cell membranes and between cells. Depolarization of the cell membrane causes VGSCs to open but also gives rise to a nonconducting state termed inactivation. Inactivation of VGSCs serves a critical physiologic function as it determines the extent of excitability of neurons and of muscle cells. Depending on the time course of development and removal of inactivation both "fast-" and "slow"-inactivated states have been described. Evidence from mutagenesis studies suggests that fast inactivation is produced by a block of the internal vestibule by a tethered inactivation particle that has been mapped to the internal linker between domains III and IV. The motion of this linker may be regulated by parts of the internal C-terminus. The molecular mechanism of slow inactivation is less clear. However, aside from a high number of mutagenesis studies, the recent availability of 3D structures of crystallized prokaryotic VGSCs offers insights into the molecular motions associated with slow inactivation. One possible scenario is that slow movements of the voltage sensors are transmitted to the external vestibule giving rise to a conformational change of this region. This molecular rearrangement is transmitted to the S6 segments giving rise to collapse of the internal vestibule.
authors: Medical University of Vienna, Vienna, Austria.
authors: V S
authors: VS
authors: Gawali
authors: Medical University of Vienna, Vienna, Austria.
authors: H
authors: H
authors: Todt
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001419:Bacteria / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020916:Conotoxins / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008012:Lidocaine / Q000737:chemistry / Q000378:metabolism; D016296:Mutagenesis; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D020916:Conotoxins; D020033:Protein Isoforms; D021122:Protein Subunits; D061566:Voltage-Gated Sodium Channels; D008012:Lidocaine
keywords: Beta subunit; Fast inactivation; Inactivation gate; Inner vestibule; Mutagenesis; Outer vestibule; Selectivity filter; Slow inactivation; Ultraslow inactivation; Voltage-gated sodium channels