Vital organs such as the muscles, heart and brain need proteins, ion channels, to function. These regulate the passage of ions such as potassium or sodium across the cell membrane by a controlled opening and closing mechanism called 'gating'.

A new study published in Nature Communications, coordinated by Sapienza and the University of Chicago, examined the Ether-à-go-Related Gene (hERG) ion channel, a voltage-dependent potassium-permeable channel that regulates heart contraction. Malfunctions of this channel are associated with Long QT Syndrome Type 2 (LQTS2), a severe heart condition that can lead to arrhythmia and even sudden death even in very young people.

The researchers discovered an unexpected chain of contacts between amino acids that links the channel sensor, which is sensitive to voltage variations, to the pore that actually determines its opening and closing. By mutating the most important amino acids of this chain, it was possible to identify, thanks to a synergy between molecular simulations and electrophysiology experiments, a new gating mechanism of a non-canonical type.

"These results," says Alberto Giacomello, study coordinator from the Department of Mechanical and Aerospace Engineering of Sapienza University of Rome ", provide new details on the mechanism of hERG channel opening and closing that are useful both for understanding the molecular causes behind LQTS2 and for designing more specific therapies to treat the condition".

References:

Noncanonical electromechanical coupling paths in cardiac hERG potassium channel - Carlos A. Z. Bassetto Jr, Flavio Costa, Carlo Guardiani, Francisco Bezanilla & Alberto Giacomello - Nat Commun 14, 1110 (2023). https://doi.org/10.1038/s41467-023-36730-7

Further Information

Alberto Giacomello
Department of Mechanical and Aerospace Engineering
alberto.giacomello@uniroma1.it