Isoenzyme-specific regulation of cardiac Kv1.5/Kv[beta]1.2 ion channel complex by protein kinase C: central role of PKC[beta]^sub II

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2014-05, Vol.387 (5), p.469
• Main Authors: Fischer, Fathima, Vonderlin, Nadine, Seyler, Claudia, Zitron, Edgar, Korkmaz, Sevil, Szabó, Gábor, Thomas, Dierk, Katus, Hugo A, Scholz, Eberhard P
• Format: Article
• Language: English
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-014-0965-5

The ultrarapidly activating delayed rectifier current, I ^sub Kur,^ is a main determinant of atrial repolarization in humans. I ^sub Kur^ and the underlying ion channel complex Kv1.5/Kv[beta]1.2 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/Kv[beta]1.2 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/Kv[beta]1.2 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/Kv[beta]1.2 ion channel complex is mainly regulated by conventional isoforms. Whereas pharmacological inhibition of PKC[alpha] with HBDDE did not attenuate the PMA-induced effect, current reduction could be prevented using inhibitors of PKC[beta]. Here, we show the isoform [beta]^sub II^ plays a central role in the PKC-dependent regulation of Kv1.5/Kv[beta]1.2 channels. These results add to the current understanding of isoenzyme-selective regulation of cardiac ion channels by protein kinases.