title: Models of HERG gating.
abstract: HERG (Kv11.1, KCNH2) is a voltage-gated potassium channel with unique gating characteristics. HERG has fast voltage-dependent inactivation, relatively slow deactivation, and fast recovery from inactivation. This combination of gating kinetics makes study of HERG difficult without using mathematical models. Several HERG models have been developed, with fundamentally different organization. HERG is the molecular basis of I(Kr), which plays a critical role in repolarization. We programmed and compared five distinct HERG models. HERG gating cannot be adequately replicated using Hodgkin-Huxley type formulation. Using Markov models, a five-state model is required with three closed, one open, and one inactivated state, and a voltage-independent step between some of the closed states. A fundamental difference between models is the presence/absence of a transition directly from the proximal closed state to the inactivated state. The only models that effectively reproduce HERG data have no direct closed-inactivated transition, or have a closed-inactivated transition that is effectively zero compared to the closed-open transition, rendering the closed-inactivation transition superfluous. Our single-channel model demonstrates that channels can inactivate without conducting with a flickering or bursting open-state. The various models have qualitative and quantitative differences that are critical to accurate predictions of HERG behavior during repolarization, tachycardia, and premature depolarizations.
authors.affiliation: Center for Cellular and Systems Electrophysiology, Gynecology-Obstetrics, State University of New York, University at Buffalo, Buffalo, New York, USA. bett@buffalo.edu
authors.forename: Glenna C L
authors.initials: GC
authors.lastname: Bett
authors.forename: Qinlian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Randall L
authors.initials: RL
authors.lastname: Rasmusson
mesh_terms: D000200:Action Potentials; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D015640:Ion Channel Gating; D008954:Models, Biological; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human