Effects of the PKC inhibitors chelerythrine and bisindolylmaleimide I (GF 109203X) on delayed rectifier K+ currents View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-12-01

AUTHORS

Gábor Harmati, Ferenc Papp, Norbert Szentandrássy, László Bárándi, Ferenc Ruzsnavszky, Balázs Horváth, Tamás Bányász, János Magyar, György Panyi, Zoltán Krasznai, Péter P. Nánási

ABSTRACT

Protein kinase C (PKC) inhibitors are useful tools for studying PKC-dependent regulation of ion channels. For this purpose, high PKC specificity is a basic requirement excluding any direct interaction between the PKC inhibitor and the ion channel. In the present study, the effects of two frequently applied PKC inhibitors, chelerythine and bisindolylmaleimide I, were studied on the rapid and slow components of the delayed rectifier K+ current (IKr and IKs) in canine ventricular cardiomyocytes and on the human ether-à-go-go-related gene (hERG) channels expressed in human embryonic kidney (HEK) cells. The whole cell version of the patch clamp technique was used in all experiments. Chelerythrine and bisindolylmaleimide I (both 1 μM) suppressed IKr in canine ventricular cells. This inhibition developed rapidly, suggesting a direct drug–channel interaction. In HEK cells heterologously expressing hERG channels, chelerythrine and bisindolylmaleimide I blocked hERG current in a concentration-dependent manner, having EC50 values of 0.11 ± 0.01 and 0.76 ± 0.04 μM, respectively. Both chelerythrine and bisindolylmaleimide I strongly modified gating kinetics of hERG—voltage dependence of activation was shifted towards more negative voltages and activation was accelerated. Deactivation was slowed by bisindolylmaleimide I but not by chelerythrine. IKs was not significantly altered by bisindolylmaleimide I and chelerythrine. No significant effect of 0.1 μM bisindolylmaleimide I or 0.1 μM PMA (PKC activator) was observed on IKr arguing against significant contribution of PKC to regulation of IKr. It is concluded that neither chelerythrine nor bisindolylmaleimide I is suitable for selective PKC blockade due to their direct blocking actions on the hERG channel. More... »

PAGES

141-148

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00210-010-0584-8

DOI

http://dx.doi.org/10.1007/s00210-010-0584-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1027178206

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21120453


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28 schema:description Protein kinase C (PKC) inhibitors are useful tools for studying PKC-dependent regulation of ion channels. For this purpose, high PKC specificity is a basic requirement excluding any direct interaction between the PKC inhibitor and the ion channel. In the present study, the effects of two frequently applied PKC inhibitors, chelerythine and bisindolylmaleimide I, were studied on the rapid and slow components of the delayed rectifier K+ current (IKr and IKs) in canine ventricular cardiomyocytes and on the human ether-à-go-go-related gene (hERG) channels expressed in human embryonic kidney (HEK) cells. The whole cell version of the patch clamp technique was used in all experiments. Chelerythrine and bisindolylmaleimide I (both 1 μM) suppressed IKr in canine ventricular cells. This inhibition developed rapidly, suggesting a direct drug–channel interaction. In HEK cells heterologously expressing hERG channels, chelerythrine and bisindolylmaleimide I blocked hERG current in a concentration-dependent manner, having EC50 values of 0.11 ± 0.01 and 0.76 ± 0.04 μM, respectively. Both chelerythrine and bisindolylmaleimide I strongly modified gating kinetics of hERG—voltage dependence of activation was shifted towards more negative voltages and activation was accelerated. Deactivation was slowed by bisindolylmaleimide I but not by chelerythrine. IKs was not significantly altered by bisindolylmaleimide I and chelerythrine. No significant effect of 0.1 μM bisindolylmaleimide I or 0.1 μM PMA (PKC activator) was observed on IKr arguing against significant contribution of PKC to regulation of IKr. It is concluded that neither chelerythrine nor bisindolylmaleimide I is suitable for selective PKC blockade due to their direct blocking actions on the hERG channel.
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35 schema:keywords C (PKC) inhibitors
36 EC50 values
37 HEK
38 IKr
39 IKs
40 PKC
41 PKC inhibitor
42 PKC inhibitor chelerythrine
43 PKC specificity
44 PKC-dependent regulation
45 PMA
46 action
47 activation
48 basic requirements
49 bisindolylmaleimide I
50 canine ventricular cardiomyocytes
51 canine ventricular cells
52 cardiomyocytes
53 cell version
54 cells
55 channels
56 chelerythine
57 chelerythrine
58 clamp technique
59 components
60 concentration-dependent manner
61 contribution
62 current
63 deactivation
64 dependence
65 direct drug–channel interaction
66 direct interaction
67 drug-channel interaction
68 effect
69 embryonic kidney cells
70 ether
71 experiments
72 gating kinetics
73 gene (hERG) channels
74 hERG
75 hERG channels
76 hERG—voltage dependence
77 high PKC specificity
78 human embryonic kidney cells
79 human ether
80 inhibition
81 inhibitor chelerythrine
82 inhibitors
83 interaction
84 ion channels
85 kidney cells
86 kinase C inhibitor
87 kinetics
88 manner
89 negative voltage
90 patch-clamp technique
91 present study
92 protein kinase C inhibitor
93 purpose
94 rectifier
95 regulation
96 regulation of IKr
97 requirements
98 selective PKC
99 significant contribution
100 significant effect
101 slow component
102 specificity
103 study
104 technique
105 tool
106 useful tool
107 values
108 ventricular cardiomyocytes
109 ventricular cells
110 version
111 voltage
112 whole cell version
113 μM PMA
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