Different protein kinase C isoenzymes mediate inhibition of cardiac rapidly activating delayed rectifier K+ current by different G-protein coupled receptors.
Br J Pharmacol
; 174(23): 4464-4477, 2017 Dec.
Article
em En
| MEDLINE
| ID: mdl-28941256
ABSTRACT
BACKGROUND AND PURPOSE:
Elevated angiotensin II (Ang II) and sympathetic activity contributes to a high risk of ventricular arrhythmias in heart disease. The rapidly activating delayed rectifier K+ current (IKr ) carried by the hERG channels plays a critical role in cardiac repolarization, and decreased IKr is involved in increased cardiac arrhythmogenicity. Stimulation of α1A -adrenoreceptors or angiotensin II AT1 receptors is known to inhibit IKr via PKC. Here, we have identified the PKC isoenzymes mediating the inhibition of IKr by activation of these two different GPCRs. EXPERIMENTALAPPROACH:
The whole-cell patch-clamp technique was used to record IKr in guinea pig cardiomyocytes and HEK293 cells co-transfected with hERG and α1A -adrenoreceptor or AT1 receptor genes. KEYRESULTS:
A broad spectrum PKC inhibitor Gö6983 (not inhibiting PKCε), a selective cPKC inhibitor Gö6976 and a PKCα-specific inhibitor peptide, blocked the inhibition of IKr by the α1A -adrenoreceptor agonist A61603. However, these inhibitors did not affect the reduction of IKr by activation of AT1 receptors, whereas the PKCε-selective inhibitor peptide did block the effect. The effects of angiotensin II and the PKCε activator peptide were inhibited in mutant hERG channels in which 17 of the 18 PKC phosphorylation sites were deleted, whereas a deletion of the N-terminus of the hERG channels selectively prevented the inhibition elicited by A61603 and the cPKC activator peptide. CONCLUSIONS AND IMPLICATIONS Our results indicated that inhibition of IKr by activation of α1A -adrenoreceptors or AT1 receptors were mediated by PKCα and PKCε isoforms respectively, through different molecular mechanisms.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteína Quinase C
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Miócitos Cardíacos
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Receptores Acoplados a Proteínas G
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Canais de Potássio de Retificação Tardia
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article