title: Accessory subunits alter the temperature sensitivity of Kv4.3 channel complexes.
abstract: In human atrial myocytes the transient outward current I(to) develops a conspicuous faster inactivation with increasing temperatures. Since β-subunits are known to modulate I(to) current kinetics, we hypothesized that the temperature sensitivity of I(to) is not only determined by the property of the ion-passing α-subunit Kv4.3 but also by its interaction with accessory β-subunits. We therefore studied the influence of the transmembrane β-subunits KCNE1, KCNE2 and DPP6 on Kv4.3/KChIP2 channels in CHO cells at room temperature and at physiological temperature. Exposure to 37°C caused a significant acceleration of the channel kinetics, whereas current densities and voltage dependences remained unaltered at 37°C compared to 23°C. However, Kv4.3/KChIP2 channels without transmembrane β-subunits showed the strongest temperature sensitivity with considerably increased rates of activation and inactivation at 37°C. KCNE2 significantly slowed the current kinetics at 37°C compared to Kv4.3/KChIP2 channels, whereas KCNE1 did not influence the channel properties at both temperatures. Interestingly, the accelerating effects of DPP6 on current kinetics described at 23°C were diminished at physiological temperature, thus at 37°C current kinetics became remarkably similar for channel complexes Kv4.3/KChIP2 with and without DPP6 isoforms. A Markov state model was developed on the basis of experimental measurements to simulate the influence of β-subunits on Kv4.3 channel complex at both temperatures. In conclusion, the remarkably fast kinetics of the native I(to) at 37°C could be reproduced by co-expressing Kv4.3, KChIP2, KCNE2 and DPP6 in CHO cells, whereas the high temperature sensitivity of human I(to) could be not mimicked.
authors.affiliation: Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstr.16-18, 04107 Leipzig, Germany. susanne.radicke@medizin.uni-leipzig.de
authors.forename: S
authors.initials: S
authors.lastname: Radicke
authors.forename: T
authors.initials: T
authors.lastname: Riedel
authors.forename: D
authors.initials: D
authors.lastname: Cotella
authors.forename: K
authors.initials: K
authors.lastname: Turnow
authors.forename: U
authors.initials: U
authors.lastname: Ravens
authors.forename: M
authors.initials: M
authors.lastname: Schaefer
authors.forename: E
authors.initials: E
authors.lastname: Wettwer
mesh_terms: D000200:Action Potentials; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008390:Markov Chains; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology; D055550:Protein Stability; D021122:Protein Subunits / Q000502:physiology*; D051672:Shal Potassium Channels / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D051672:Shal Potassium Channels; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases