title: A temperature-dependent in silico model of the human ether-à-go-go-related (hERG) gene channel.
abstract: BACKGROUND
  Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-à-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures. To accommodate current industry safety pharmacology practices for measuring hERG channel activity, an in silico model of hERG channel that allows for the extrapolation of hERG assay data across different temperatures is desired. Because temperature may have an effect on both channel gating and drug binding rate, such models may need to have two components: a base model dealing with temperature-dependent gating changes without drug, and a pharmacodynamic component simulating temperature-dependent drug binding kinetics. As a first step, a base mode that can capture temperature effects on hERG channel gating without drug is needed.
  
  
  RESULTS
  To meet this need for a temperature-dependent base model, a Markov model of the hERG channel with state transition rates explicitly dependent on temperature was developed and calibrated using data from a variety of published experiments conducted over a range of temperatures. The model was able to reproduce observed temperature-dependent changes in key channel gating properties and also to predict the results obtained in independent sets of new experiments.
  
  
  CONCLUSIONS
  This new temperature-sensitive model of hERG gating represents an attempt to improve the predictivity of safety pharmacology testing by enabling the translation of room temperature hERG assay data to more physiological conditions. With further development, this model can be incorporated into the CiPA paradigm and also be used as a tool for developing insights into the thermodynamics of hERG channel gating mechanisms and the temperature-dependence of hERG channel block by drugs.
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, United States. Electronic address: Zhihua.li@fda.hhs.gov.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, United States.
authors.forename: Sara
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, United States.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, United States.
authors.forename: Phu N
authors.initials: PN
authors.lastname: Tran
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Wu
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Colatsky
mesh_terms: D000465:Algorithms; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D002138:Calibration; D003198:Computer Simulation; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008390:Markov Chains; D008564:Membrane Potentials / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012449:Safety; D013696:Temperature
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D026902:Potassium Channel Blockers
keywords: CiPA; Kv11.1; Markov model; Methods; Temperature; hERG