title: Stabilization of Kv1.5 channel protein by the inotropic agent olprinone.
abstract: Olprinone is an inotropic agent that inhibits phosphodiesterase (PDE) III and causes vasodilation. Olprinone has been shown to be less proarrhythmic and possibly affect expression of functional Kv1.5 channels that confer the ultra-rapid delayed-rectifier K+ channel current (IKur) responsible for action potential repolarization. To reveal involvement of Kv1.5 channels in the less arrhythmic effect of olprinone, we examined effects of the agent on the stability of Kv1.5 channel proteins expressed in COS7 cells. Olprinone at 30-1000 nM increased the protein level of Kv1.5 channels in a concentration-dependent manner. Chase experiments showed that olprinone delayed degradation of Kv1.5 channels. Olprinone increased the immunofluorescent signal of Kv1.5 channels in the endoplasmic reticulum (ER) and Golgi apparatus as well as on the cell surface. Kv1.5-mediated membrane currents, measured as 4-aminopyridine-sensitive currents, were increased by olprinone without changes in their activation kinetics. A protein transporter inhibitor, colchicine, abolished the olprinone-induced increase of Kv.1.5-mediated currents. The action of olprinone was inhibited by 4-aminopyridine, and was not mimicked by the application of 8-Bromo-cAMP. Taken together, we conclude that olprinone stabilizes Kv1.5 proteins at the ER through an action as a chemical chaperone, and thereby increases the density of Kv1.5 channels on the cell membrane. The enhancement of Kv1.5 currents could underlie less arrhythmogenicity of olprinone.
authors.affiliation: Department of Anesthesiology, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Endo
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0268, Japan. Electronic address: yasu@kanazawa-med.ac.jp.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Kurata
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Notsu
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Peili
authors.initials: P
authors.lastname: Li
authors.affiliation: Center for Promoting Next-Generation Highly Advanced Medicine, Tottori University Hospital, 36-1 Nishi-cho, Yonago 683-8504, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Morikawa
authors.affiliation: Department of Cardiovascular Medicine, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Cardiovascular Medicine, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ogura
authors.affiliation: Department of Cardiovascular Medicine, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Miake
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shirayoshi
authors.affiliation: Department of Biological Regulation, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.affiliation: Department of Human Genome Science, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Department of Cardiology, Toranomon Hospital, Tokyo 105-8470, Japan.
authors.forename: Masanari
authors.initials: M
authors.lastname: Kuwabara
authors.affiliation: Department of Cardiovascular Medicine, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Anesthesiology, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
mesh_terms: D000818:Animals; D019556:COS Cells; D002316:Cardiotonic Agents / Q000378:metabolism* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000378:metabolism* / Q000494:pharmacology*; D051666:Kv1.5 Potassium Channel / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D055550:Protein Stability / Q000187:drug effects; D011728:Pyridones / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D007093:Imidazoles; D051666:Kv1.5 Potassium Channel; D011728:Pyridones; C059498:olprinone
keywords: Chemical chaperone; Kv1.5 channel; Olprinone