PKC inhibition results in a Kv 1.5 + Kv ?1.3 pharmacology closer to Kv 1.5 channels.
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ABSTRACT: The Kv ?1.3 subunit modifies the gating and pharmacology of Kv 1.5 channels in a PKC-dependent manner, decreasing channel sensitivity to bupivacaine- and quinidine-mediated blockade. Cardiac Kv 1.5 channels associate with receptor for activated C kinase 1 (RACK1), the Kv ?1.3 subunit and different PKC isoforms, resulting in the formation of a functional channelosome. The aim of the present study was to investigate the effects of PKC inhibition on bupivacaine and quinidine block of Kv 1.5 + Kv ?1.3 channels.HEK293 cells were transfected with Kv 1.5 + Kv ?1.3 channels, and currents were recorded using the whole-cell configuration of the patch-clamp technique. PKC inhibition was achieved by incubating the cells with either calphostin C or bisindolylmaleimide II and the effects of bupivacaine and quinidine were analysed.The voltage-dependent inactivation of Kv 1.5 + Kv ?1.3 channels and their pharmacological behaviour after PKC inhibition with calphostin C were similar to those displayed by Kv 1.5 channels alone. Indeed, the IC50 values for bupivacaine were similar in cells whose PKC was inhibited with calphostin C or bisindolylmaleimide II. Similar results were also observed in the presence of quinidine.The finding that the voltage-dependence of inactivation and the pharmacology of Kv 1.5 + Kv ?1.3 channels after PKC inhibition resembled that observed in Kv 1.5 channels suggests that both processes are dependent on PKC-mediated phosphorylation. These results may have clinical relevance in diseases that are characterized by alterations in kinase activity.
SUBMITTER: Macias A
PROVIDER: S-EPMC4294114 | biostudies-other | 2014 Nov
REPOSITORIES: biostudies-other
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