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PKC inhibition results in a K v 1.5 + K v β 1.3 pharmacology closer to K v 1.5 channels
Author(s) -
Macías A,
Cruz A,
Prieto A,
Peraza D A,
Tamkun M M,
González T,
Valenzuela C
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12822
Subject(s) - calphostin c , bisindolylmaleimide , protein kinase c , quinidine , chemistry , pharmacology , patch clamp , biophysics , kinase , biology , biochemistry , receptor
Background and Purpose The K v β 1.3 subunit modifies the gating and pharmacology of K v 1.5 channels in a PKC ‐dependent manner, decreasing channel sensitivity to bupivacaine‐ and quinidine‐mediated blockade. Cardiac K v 1.5 channels associate with receptor for activated C kinase 1 (RACK1), the K v β 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 K v 1.5 + K v β1.3 channels. Experimental Approach HEK 293 cells were transfected with K v 1.5 + K v β 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. Key Results The voltage‐dependent inactivation of K v 1.5 + K v β 1.3 channels and their pharmacological behaviour after PKC inhibition with calphostin C were similar to those displayed by K v 1.5 channels alone. Indeed, the IC 50 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. Conclusions and Implications The finding that the voltage‐dependence of inactivation and the pharmacology of K v 1.5 + K v β 1.3 channels after PKC inhibition resembled that observed in K v 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.