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Isoleucine gate blocks K+ conduction in C-type inactivation

Authors :
Werner Treptow
Yichen Liu
Carlos AZ Bassetto
Bernardo I Pinto
Joao Antonio Alves Nunes
Ramon Mendoza Uriarte
Christophe J Chipot
Francisco Bezanilla
Benoit Roux
Source :
eLife, Vol 13 (2024)
Publication Year :
2024
Publisher :
eLife Sciences Publications Ltd, 2024.

Abstract

Many voltage-gated potassium (Kv) channels display a time-dependent phenomenon called C-type inactivation, whereby prolonged activation by voltage leads to the inhibition of ionic conduction, a process that involves a conformational change at the selectivity filter toward a non-conductive state. Recently, a high-resolution structure of a strongly inactivated triple-mutant channel kv1.2-kv2.1-3m revealed a novel conformation of the selectivity filter that is dilated at its outer end, distinct from the well-characterized conductive state. While the experimental structure was interpreted as the elusive non-conductive state, our molecular dynamics simulations and electrophysiological measurements show that the dilated filter of kv1.2-kv2.1-3m is conductive and, as such, cannot completely account for the inactivation of the channel observed in the structural experiments. The simulation shows that an additional conformational change, implicating isoleucine residues at position 398 along the pore lining segment S6, is required to effectively block ion conduction. The I398 residues from the four subunits act as a state-dependent hydrophobic gate located immediately beneath the selectivity filter. These observations are corroborated by electrophysiological experiments showing that ion permeation can be resumed in the kv1.2-kv2.1-3m channel when I398 is mutated to an asparagine—a mutation that does not abolish C-type inactivation since digitoxin (AgTxII) fails to block the ionic permeation of kv1.2-kv2.1-3m_I398N. As a critical piece of the C-type inactivation machinery, this structural feature is the potential target of a broad class of quaternary ammonium (QA) blockers and negatively charged activators thus opening new research directions toward the development of drugs that specifically modulate gating states of Kv channels.

Details

Language :
English
ISSN :
2050084X and 49798626
Volume :
13
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.33e5fb7e585748c49798626eae8ebd47
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.97696