title: Molecular coupling in the human ether-a-go-go-related gene-1 (hERG1) K+ channel inactivation pathway.
abstract: Emerging evidence suggests that K(+) channel inactivation involves coupling between residues in adjacent regions of the channel. Human ether-a-go-go-related gene-1 (hERG1) K(+) channels undergo a fast inactivation gating process that is crucial for maintaining electrical stability in the heart. The molecular mechanisms that drive inactivation in hERG1 channels are unknown. Using alanine scanning mutagenesis, we show that a pore helix residue (Thr-618) that points toward the S5 segment is critical for normal inactivation gating. Amino acid substitutions at position 618 modulate the free energy of inactivation gating, causing enhanced or reduced inactivation. Mutation of an S5 residue that is predicted to be adjacent to Thr-618 (W568L) abolishes inactivation and alters ion selectivity. The introduction of the Thr-618-equivalent residue in Kv1.5 enhances inactivation. Molecular dynamic simulations of the Kv1.2 tetramer reveal van der Waals coupling between hERG1 618- and 568-equivalent residues and a significant increase in interaction energies when threonine is introduced at the 618-equivalent position. We propose that coupling between the S5 segment and pore helix may participate in the inactivation process in hERG1 channels.
authors: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112, USA.
authors: Tania
authors: T
authors: Ferrer
authors: Julio F
authors: JF
authors: Cordero-Morales
authors: Marcelo
authors: M
authors: Arias
authors: Eckhard
authors: E
authors: Ficker
authors: David
authors: D
authors: Medovoy
authors: Eduardo
authors: E
authors: Perozo
authors: Martin
authors: M
authors: Tristani-Firouzi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008958:Models, Molecular; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D017433:Protein Structure, Secondary; D014982:Xenopus laevis
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D009124:Muscle Proteins