Channelpedia

A molecular switch between the outer and the inner vestibules of the voltage-gated Na+ channel.


Authors: Touran Zarrabi, René Cervenka, Walter Sandtner, Peter Lukacs, Xaver Koenig, Karlheinz Hilber, Markus Mille, Gregory M Lipkind, Harry A Fozzard, Hannes Todt

Journal, date & volume: , 2010 Oct 6 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20926383

Channelpedia reference in: Nav1.4

Abstract
Voltage-gated ion channels are transmembrane proteins that undergo complex conformational changes during their gating transitions. Both functional and structural data from K+ channels suggest that extracellular and intracellular parts of the pore communicate with each other via a trajectory of interacting amino acids. No crystal structures are available for voltage-gated Na+ channels but functional data suggest a similar intramolecular communication involving the inner and outer vestibules. However, the mechanism of such communication is unknown. Here, we report that amino acid I1575 in the middle of transmembrane segment 6 of domain IV (DIV-S6) in the rNaV1.4 channel may act as molecular switch allowing for interaction between outer and inner vestibule. Cysteine scanning mutagenesis of the internal part of DIV-S6 revealed that only mutations at site 1575 rescued the channel from a unique kinetic state (ultra-slow inactivation, IUS) produced by the mutation K1237E in the selectivity filter. A similar effect was seen with I1575A. Previously, we reported that conformational changes of both the internal and the external vestibule are involved in the generation of IUS. The fact that mutations at site 1575 modulate IUS produced by K1237E strongly suggests an interaction between these sites. Our data confirm a previously published molecular model in which I1575 of DIV-S6 is in close proximity to K1237 of the selectivity filter. Furthermore, these functional data define the position of the selectivity filter relative to the adjacent S6 segments within the ionic permeation pathway.