Noncanonical electromechanical coupling paths in cardiac hERG potassium channel

Carlos A. Z. Bassetto, Flavio Costa, Carlo Guardiani, Francisco Bezanilla () and Alberto Giacomello ()
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Carlos A. Z. Bassetto: The University of Chicago
Flavio Costa: Sapienza Università di Roma
Carlo Guardiani: Sapienza Università di Roma
Francisco Bezanilla: The University of Chicago
Alberto Giacomello: Sapienza Università di Roma

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Voltage-gated potassium channels are involved in many physiological processes such as nerve impulse transmission, the heartbeat, and muscle contraction. However, for many of them the molecular determinants of the gating mechanism remain elusive. Here, using a combination of theoretical and experimental approaches, we address this problem focusing on the cardiac hERG potassium channel. Network analysis of molecular dynamics trajectories reveals the presence of a kinematic chain of residues that couples the voltage sensor domain to the pore domain and involves the S4/S1 and S1/S5 subunit interfaces. Mutagenesis experiments confirm the role of these residues and interfaces in the activation and inactivation mechanisms. Our findings demonstrate the presence of an electromechanical transduction path crucial for the non-domain-swapped hERG channel gating that resembles the noncanonical path identified in domain-swapped K+ channels.

Date: 2023
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DOI: 10.1038/s41467-023-36730-7

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