{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Schreiber JA"],"funding":["Deutsche Forschungsgemeinschaft","NHLBI NIH HHS","NINDS NIH HHS"],"pagination":["301"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8976019"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["5(1)"],"pubmed_abstract":["Loss-of-function mutations in K<sub>v</sub>7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic I<sub>Ks</sub> modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative (R)-L3 potently activates K<sub>v</sub>7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by (R)-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we show that (R)-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identify novel (R)-L3-interacting key residues in the lower S4-segment of K<sub>v</sub>7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments."],"journal":["Communications biology"],"pubmed_title":["A benzodiazepine activator locks K<sub>v</sub>7.1 channels open by electro-mechanical uncoupling."],"pmcid":["PMC8976019"],"funding_grant_id":["DFG-Se 1077-13/1-3","R01 HL126774","Graduate Cschool Chembion","R01 NS092570"],"pubmed_authors":["Ritter N","Beller Z","Moller M","Cui J","Schmitt N","Seebohm G","Meuth SG","Becker S","Zaydman M","Silva J","Wrobel E","Zhao L","Hou P","Dufer M","Strutz-Seebohm N","Schreiber JA","Shi J","Wunsch B","Decher N"],"additional_accession":[]},"is_claimable":false,"name":"A benzodiazepine activator locks K<sub>v</sub>7.1 channels open by electro-mechanical uncoupling.","description":"Loss-of-function mutations in K<sub>v</sub>7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic I<sub>Ks</sub> modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative (R)-L3 potently activates K<sub>v</sub>7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by (R)-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we show that (R)-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identify novel (R)-L3-interacting key residues in the lower S4-segment of K<sub>v</sub>7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Apr","modification":"2026-05-09T23:43:41.684Z","creation":"2025-04-04T22:14:05.474Z"},"accession":"S-EPMC8976019","cross_references":{"pubmed":["35365746"],"doi":["10.1038/s42003-022-03229-8"]}}