PKC inhibition results in a Kv 1.5 + Kvβ 1.3 pharmacology closer to Kv 1.5 channels

Background and PurposeTheKvβ1.3 subunit modifies the gating and pharmacology ofKv1.5 channels in aPKC‐dependent manner, decreasing channel sensitivity to bupivacaine‐ and quinidine‐mediated blockade. CardiacKv1.5 channels associate with receptor for activated C kinase 1 (RACK1), theKvβ1.3 subunit and differentPKCisoforms, resulting in the formation of a functional channelosome. The aim of the present study was to investigate the effects ofPKCinhibition on bupivacaine and quinidine block ofKv1.5 +Kvβ1.3 channels.Experimental ApproachHEK293 cells were transfected withKv1.5 +Kvβ1.3 channels, and currents were recorded using the whole‐cell configuration of the patch‐clamp technique.PKCinhibition was achieved by incubating the cells with either calphostinCor bisindolylmaleimideIIand the effects of bupivacaine and quinidine were analysed.Key ResultsThe voltage‐dependent inactivation ofKv1.5 +Kvβ1.3 channels and their pharmacological behaviour afterPKCinhibition with calphostinCwere similar to those displayed byKv1.5 channels alone. Indeed, theIC50values for bupivacaine were similar in cells whosePKCwas inhibited with calphostinCor bisindolylmaleimideII. Similar results were also observed in the presence of quinidine.Conclusions and ImplicationsThe finding that the voltage‐dependence of inactivation and the pharmacology ofKv1.5 +Kvβ1.3 channels afterPKCinhibition resembled that observed inKv1.5 channels suggests that both processes are dependent onPKC‐mediated phosphorylation. These results may have clinical relevance in diseases that are characterized by alterations in kinase activity.