title: A model of the interaction between N-type and C-type inactivation in Kv1.4 channels.
abstract: Kv1.4 channels are Shaker-related voltage-gated potassium channels with two distinct inactivation mechanisms. Fast N-type inactivation operates by a ball-and-chain mechanism. Slower C-type inactivation is not so well defined, but involves intracellular and extracellular conformational changes of the channel. We studied the interaction between inactivation mechanisms using two-electrode voltage-clamp of Kv1.4 and Kv1.4ΔN (amino acids 2-146 deleted to remove N-type inactivation) heterologously expressed in Xenopus oocytes. We manipulated C-type inactivation by introducing a lysine-tyrosine point mutation (K532Y, equivalent to Shaker T449Y) that diminishes C-type inactivation. We used experimental data to develop a comprehensive computer model of Kv1.4 channels to determine the interaction between activation and N- and C-type inactivation mechanisms needed to replicate the experimental data. C-type inactivation began at lower voltage preactivated states, whereas N-type inactivation was coupled directly to the open state. A model with distinct N- and C-type inactivated states was not able to reproduce experimental data, and direct transitions between N- and C-type inactivated states were required, i.e., there is coupling between N- and C-type inactivated states. C-type inactivation is the rate-limiting step determining recovery from inactivation, so understanding C-type inactivation, and how it is coupled to N-type inactivation, is critical in understanding how channels act to repetitive stimulation.
authors.affiliation: Department of Gynecology-Obstetrics, The State University of New York, University at Buffalo, Buffalo, New York, USA.
authors.forename: Glenna C L
authors.initials: GC
authors.lastname: Bett
authors.forename: Isidore
authors.initials: I
authors.lastname: Dinga-Madou
authors.forename: Qinlian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Vladimir E
authors.initials: VE
authors.lastname: Bondarenko
authors.forename: Randall L
authors.initials: RL
authors.lastname: Rasmusson
mesh_terms: D000818:Animals; D005289:Ferrets; D015640:Ion Channel Gating; D007700:Kinetics; D051665:Kv1.4 Potassium Channel / Q000378:metabolism*; D008954:Models, Biological; D014982:Xenopus laevis
chemical_list: D051665:Kv1.4 Potassium Channel