title: Hydrogen bonds as molecular timers for slow inactivation in voltage-gated potassium channels.
abstract: Voltage-gated potassium (Kv) channels enable potassium efflux and membrane repolarization in excitable tissues. Many Kv channels undergo a progressive loss of ion conductance in the presence of a prolonged voltage stimulus, termed slow inactivation, but the atomic determinants that regulate the kinetics of this process remain obscure. Using a combination of synthetic amino acid analogs and concatenated channel subunits we establish two H-bonds near the extracellular surface of the channel that endow Kv channels with a mechanism to time the entry into slow inactivation: an intra-subunit H-bond between Asp447 and Trp434 and an inter-subunit H-bond connecting Tyr445 to Thr439. Breaking of either interaction triggers slow inactivation by means of a local disruption in the selectivity filter, while severing the Tyr445-Thr439 H-bond is likely to communicate this conformational change to the adjacent subunit(s). DOI: http://dx.doi.org/10.7554/eLife.01289.001.
authors: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
authors: Stephan A
authors: SA
authors: Pless
authors: Jason D
authors: JD
authors: Galpin
authors: Ana P
authors: AP
authors: Niciforovic
authors: Harley T
authors: HT
authors: Kurata
authors: Christopher A
authors: CA
authors: Ahern
mesh_terms: D000595:Amino Acid Sequence; D006860:Hydrogen Bonding; D015640:Ion Channel Gating; D008969:Molecular Sequence Data; D015221:Potassium Channels / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
chemical_list: D015221:Potassium Channels
keywords: channel inactivation; hydrogen bonds; ion channel gating; molecular timers; neuroscience; unnatural amino acids