title: Closed-state inactivation involving an internal gate in Kv4.1 channels modulates pore blockade by intracellular quaternary ammonium ions.
abstract: Voltage-gated K(+) (Kv) channel activation depends on interactions between voltage sensors and an intracellular activation gate that controls access to a central pore cavity. Here, we hypothesize that this gate is additionally responsible for closed-state inactivation (CSI) in Kv4.x channels. These Kv channels undergo CSI by a mechanism that is still poorly understood. To test the hypothesis, we deduced the state of the Kv4.1 channel intracellular gate by exploiting the trap-door paradigm of pore blockade by internally applied quaternary ammonium (QA) ions exhibiting slow blocking kinetics and high-affinity for a blocking site. We found that inactivation gating seemingly traps benzyl-tributylammonium (bTBuA) when it enters the central pore cavity in the open state. However, bTBuA fails to block inactivated Kv4.1 channels, suggesting gated access involving an internal gate. In contrast, bTBuA blockade of a Shaker Kv channel that undergoes open-state P/C-type inactivation exhibits fast onset and recovery inconsistent with bTBuA trapping. Furthermore, the inactivated Shaker Kv channel is readily blocked by bTBuA. We conclude that Kv4.1 closed-state inactivation modulates pore blockade by QA ions in a manner that depends on the state of the internal activation gate.
authors: Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience at Thomas Jefferson University, Philadelphia, PA, USA.|Graduate Program in Molecular Physiology &Biophysics, Sidney Kimmel Medical College and College of Biomedical Sciences at Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Jeffrey D
authors: JD
authors: Fineberg
authors: Department of Biophysics &Cell Biology, Faculty of Medicine University of Debrecen, 4032 Debrecen, Hungary.
authors: Tibor G
authors: TG
authors: Szanto
authors: Department of Biophysics &Cell Biology, Faculty of Medicine University of Debrecen, 4032 Debrecen, Hungary.|MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM University of Debrecen, 4032 Debrecen, Hungary.
authors: Gyorgy
authors: G
authors: Panyi
authors: Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience at Thomas Jefferson University, Philadelphia, PA, USA.|Graduate Program in Molecular Physiology &Biophysics, Sidney Kimmel Medical College and College of Biomedical Sciences at Thomas Jefferson University, Philadelphia, PA 19107, USA.|Vickie and Jack Farber Institute for Neuroscience at Thomas Jefferson University,Philadelphia, PA, USA.
authors: Manuel
authors: M
authors: Covarrubias
mesh_terms: D000818:Animals; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D051672:Shal Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000644:Quaternary Ammonium Compounds; D051672:Shal Potassium Channels; C090284:benzyltributylammonium