PKC inhibition results in a Kv1.5 + Kvβ1.3 pharmacology closer to Kv1.5 channels. (5th September 2014)

• Record Type: Journal Article
• Authors: Macías, A; de la Cruz, A; Prieto, A; Peraza, D A; Tamkun, M M; González, T; Valenzuela, C
• Is Part Of: British journal of pharmacology. Volume 171:Number 21(2014:Nov.)
• Page Start: 4914
• Page End: 4926
• Publication Date: 2014-09-05
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12822
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12822-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The K<sub>v</sub>β1.3 subunit modifies the gating and pharmacology of K<sub>v</sub>1.5 channels in a PKC‐dependent manner, decreasing channel sensitivity to bupivacaine‐ and quinidine‐mediated blockade. Cardiac K<sub>v</sub>1.5 channels associate with receptor for activated C kinase 1 (RACK1), the K<sub>v</sub>β1.3 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<sub>v</sub>1.5 + K<sub>v</sub>β1.3 channels.</p> </sec> <sec id="bph12822-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>HEK293 cells were transfected with K<sub>v</sub>1.5 + K<sub>v</sub>β1.3 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.</p> </sec> <sec id="bph12822-sec-0003" sec-type="section"> <title>Key Results</title> <p>The voltage‐dependent inactivation of K<sub>v</sub>1.5 + K<sub>v</sub>β1.3 channels and their pharmacological behaviour after PKC inhibition with calphostin C were similar to those displayed by K<sub>v</sub>1.5 channels alone. Indeed, the IC<sub>50</sub> 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.</p> </sec> <sec id="bph12822-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>The finding that the voltage‐dependence of inactivation and the pharmacology of K<sub>v</sub>1.5 + K<sub>v</sub>β1.3 channels after PKC inhibition resembled that observed in K<sub>v</sub>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.</p> </sec> </abstract>