title: Isoenzyme-specific regulation of cardiac Kv1.5/Kvβ1.2 ion channel complex by protein kinase C: central role of PKCβII.
abstract: The ultrarapidly activating delayed rectifier current, I(Kur), is a main determinant of atrial repolarization in humans. I(Kur) and the underlying ion channel complex Kv1.5/Kvβ1.2 are negatively regulated by protein kinase C. However, the exact mode of action is only incompletely understood. We therefore analyzed isoenzyme-specific regulation of the Kv1.5/Kvβ1.2 ion channel complex by PKC. Cloned ion channel subunits were heterologously expressed in Xenopus oocytes, and measurements were performed using the double-electrode voltage-clamp technique. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) resulted in a strong reduction of Kv1.5/Kvβ1.2 current. This effect could be prevented using the PKC inhibitor staurosporine. Using the bisindolylmaleimide Ro-31-8220 as an inhibitor and ingenol as an activator of the conventional PKC isoforms, we were able to show that the Kv1.5/Kvβ1.2 ion channel complex is mainly regulated by conventional isoforms. Whereas pharmacological inhibition of PKCα with HBDDE did not attenuate the PMA-induced effect, current reduction could be prevented using inhibitors of PKCβ. Here, we show the isoform βII plays a central role in the PKC-dependent regulation of Kv1.5/Kvβ1.2 channels. These results add to the current understanding of isoenzyme-selective regulation of cardiac ion channels by protein kinases.
authors.affiliation: Department of Internal Medicine III (Cardiology), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Fathima
authors.initials: F
authors.lastname: Fischer
authors.forename: Nadine
authors.initials: N
authors.lastname: Vonderlin
authors.forename: Claudia
authors.initials: C
authors.lastname: Seyler
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
authors.forename: Sevil
authors.initials: S
authors.lastname: Korkmaz
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
mesh_terms: D000818:Animals; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D051663:Kv1.2 Potassium Channel / Q000502:physiology*; D051666:Kv1.5 Potassium Channel / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D011485:Protein Binding; D064546:Protein Kinase C beta / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014981:Xenopus
chemical_list: D007527:Isoenzymes; D051663:Kv1.2 Potassium Channel; D051666:Kv1.5 Potassium Channel; D064546:Protein Kinase C beta; D013755:Tetradecanoylphorbol Acetate