Key result
Partial K+ ion dehydration at the KCNQ1 cavity constriction enables permeation but impedes ion flow.
Why the study?
Cryo-EM structures thought to represent the open state of KCNQ1 feature a cavity region not wide enough to accommodate hydrated K+, raising questions about the mechanisms of ion permeation.
The study reveals that partial dehydration allows K+ ions to pass through the narrow KCNQ1 channel cavity, explaining how pathogenic mutations in this region reduce channel conductance.
Mechanistic insight into KCNQ1 permeation may guide variant modeling; leaves open translation to human arrhythmias or therapies.
KCNQ1 potassium channels play a pivotal role in the physiology and pathophysiology of several human excitable and epithelial tissues. The latest cryo-electron microscopy (cryo-EM) structures provide unique insights into channel function and pharmacology, opening avenues for different therapeutic strategies against human diseases associated with KCNQ1 mutations. However, these structures also raise fundamental questions about the mechanisms of ion permeation. Cryo-EM structures thought to represent the open state of the channel feature a cavity region not wide enough for accommodation of hydrated K + . To understand how K + passes through the cavity constriction, we utilized microsecond-scale molecular dynamics (MD) simulations using the KCNQ1/KCNE3 cryo-EM structure, characterized mutants at the G345 residue situated at the narrowest point of the cavity, and recorded single channels. The findings indicate that ions become partially dehydrated at the constriction, which enables permeation. MD simulations demonstrate that the constriction can impede the flow of ions through the channel’s pore, a finding that is corroborated by mutational screening and single-channel recordings. Reduced channel conductance is the key mechanism underlying reported pathological KCNQ1 mutations at or near the constriction site.
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Mkrtchyan et al. (2024) studied KCNQ1 mutations. Molecular dynamics simulations and mutational screening was evaluated on Mechanism of ion permeation through the cavity constriction. Molecular dynamics simulations and single-channel recordings reveal that K+ ions become partially dehydrated at the KCNQ1 cavity constriction, enabling permeation but impeding ion flow.
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