Different protein kinase C isoenzymes mediate inhibition of cardiac rapidly activating delayed rectifier K<sup>+</sup> current by different G‐protein coupled receptors

Liu, Xueli; Wang, Yuhong; Zhang, Hua; Shen, Li; Xu, Yancheng

doi:10.1111/bph.14049

Cited by 13 publications

(20 citation statements)

References 41 publications

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“…4, A and B). This observation is consistent with previous literature investigating acute PKC activation (Thomas et al, 2003;Cockerill et al, 2007;Wang et al, 2008Wang et al, , 2009Liu et al, 2017). Our results further demonstrated that PKC-mediated I hERG inhibition is slowly reversible.…”

Section: Discussionsupporting

confidence: 94%

“…We investigated the molecular mechanisms underlying PMA-mediated I hERG reduction. Previous studies have suggested that the N terminus of hERG is required for PKC-mediated I hERG reduction (Cockerill et al, 2007;Liu et al, 2017). We obtained novel evidence that the N terminus is involved in PMA-mediated I hERG reduction.…”

Section: Resultsmentioning

confidence: 51%

“…It has been recognized that sympathetic activation related to physical or emotional stress can exacerbate cardiac events in patients with LQTS (Wilde et al, 1999;Schwartz et al, 2001;Winter et al, 2018). To that end, PKC is under investigation as a potential link between stress conditions and reduced hERG function; however, controversial effects of PKC on hERG function have been reported (Thomas et al, 2003;Cockerill et al, 2007;Wang et al, 2008Wang et al, , 2009Wang et al, , 2014Chen et al, 2010;Krishnan et al, 2012;Liu et al, 2017). By investigating the effects of PKC activation on both hERG current and expression on a time scale ranging from minutes to hours, our data, for the first time, uncovered that PKC differentially regulates hERG protein expression and function; PKC activation chronically enhances channel expression (hours) through delaying channel degradation while inhibiting channel function with a faster time course (tens of minutes) through a mechanism that involves the N terminus of the channel.…”

Section: Discussionmentioning

confidence: 99%

“…It was also reported that chronic (hours) PKC activation enhances I Kr in guinea pig ventricular myocytes owing to altered C-type inactivation (Heath and Terrar, 2000), as well as hERG expression and I hERG in hERG-expressing HEK cells (Chen et al, 2010;Krishnan et al, 2012). Several studies, however, have demonstrated that acute (minutes) activation of PKC inhibits I hERG and I Kr (Cockerill et al, 2007;Wang et al, 2008Wang et al, , 2009Liu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Differential Regulation of Human Ether-à-Go-Go–Related Gene (hERG) Current and Expression by Activation of Protein Kinase C

Sutherland-Deveen

Wang

Lamothe

et al. 2019

Molecular Pharmacology

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The human ether-à-go-go-related gene (hERG) encodes the channel that conducts the rapidly activating delayed rectifier potassium current (I Kr) in the heart. Reduction in I Kr causes long QT syndrome, which can lead to fatal arrhythmias triggered by stress. One potential link between stress and hERG function is protein kinase C (PKC) activation; however, seemingly conflicting results regarding PKC regulation of hERG have been reported. We investigated the effects of PKC activation using phorbol 12-myristate 13-acetate (PMA) on hERG channels expressed in human embryonic kidney cell line 293 (HEK293) cells and I Kr in isolated neonatal rat ventricular myocytes. Acute activation of PKC by PMA (30 nM, 30 minutes) reduced both hERG current (I hERG) and I Kr. Chronic activation of PKC by PMA (30 nM, 16 hours) increased I Kr in cardiomyocytes and the expression level of hERG proteins; however, chronic (30 nM, 16 hours) PMA treatment decreased I hERG , which became larger than untreated control I hERG after PMA removal for 4 hours. Deletion of amino acid residues 2-354 (D2-354 hERG) or 1-136 of the N terminus (DN 136 hERG) abolished acute PMA (30 nM, 30 minutes)-mediated I hERG reduction. In contrast to wild-type hERG channels, chronic activation of PKC by PMA (30 nM, 16 hours) increased both D2-354 hERG and DN136 hERG expression levels and currents. The increase in hERG protein was associated with PKC-induced phosphorylation (inhibition) of Nedd4-2, an E3 ubiquitin ligase that mediates hERG degradation. We conclude that PKC regulates hERG in a balanced manner, increasing expression through inhibiting Nedd4-2 while decreasing current through targeting a site(s) within the N terminus.

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Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Differential Regulation of Human Ether-à-Go-Go–Related Gene (hERG) Current and Expression by Activation of Protein Kinase C

Sutherland-Deveen

Wang

Lamothe

et al. 2019

Molecular Pharmacology

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“…Goe 6983 (10 −6 mol·L −1 at the serosal side; Table 2), another broad spectrum inhibitor of PKCs (Liu, Wang, Zhang, Shen, & Xu, 2017).…”

Section: Missing Evidence For Ionotropic Function Of Nicotinic Recementioning

confidence: 99%

Evidence for metabotropic function of epithelial nicotinic cholinergic receptors in rat colon

Lottig

Bader

Jiménez

et al. 2019

British J Pharmacology

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Background and Purpose ACh exerts its actions via nicotinic (nAChR) and muscarinic receptors. In the peripheral nervous system, ionotropic nAChR mediate responses in excitable cells. However, recent studies demonstrate the expression of nAChR in the colonic epithelium, which are coupled to an induction of Cl− secretion via activation of the Na+‐K+‐pump. Experimental Approach In order to find out whether these epithelial nAChR function as ionotropic receptors, intracellular microelectrode and imaging experiments were performed in isolated crypts from rat colon. Apically permeabilized epithelia were used to measure pump current across the basolateral membrane. Key Results Imaging experiments with the Na+‐sensitive dye SBFI revealed that nicotine induced a decrease in the cytosolic Na+ concentration concomitant with a fall in the cytosolic Ca2+ concentration in about 50% of the cells. as shown in fura‐2 experiments. Nicotine hyperpolarized the membrane by 6.4 ± 2.1 mV. These observations contradict the assumption that epithelial nAChR function as ligand‐gated non‐selective cation channels. The decrease in the cytosolic Na+ concentration was strongly delayed, when the Na+‐K+‐pump was inhibited by scilliroside. Ussing chamber experiments revealed a strong dependence of the nicotine‐induced pump current on the presence of Ca2+, and chelation of cytosolic Ca2+ with BAPTA prevented the fall in the cytosolic Na+ concentration in SBFI‐loaded crypts. Inhibition of PKC with GF 109203X or Goe 6983 significantly reduced the nicotine‐induced pump current. Conclusions and Implications These results suggest that epithelial nAChR activate the Na+‐K+‐pump via a PKC dependent on a sufficient cytosolic Ca2+ concentration.

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Isolation and culture of vascular smooth muscle cells from rat placenta

Wang

Yan

et al. 2018

Journal Cellular Physiology

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We developed a new separation method for isolating placental vascular smooth muscle cells (PVSMCs) from a rat in this study. Our method used the magnetic force between a magnet and ferrous ferric oxide (Fe3O 4) to make the separation and extraction processes easier and more efficient. From the first to sixth generation, the cells isolated using this protocol were identified as smooth muscle cells (SMCs) by their immunoreactivity to the SMC markers and by the “hill and valley” morphology. PVSMCs were exposed to angiotensin II (1 μmol/L) and resulted in sharply increased intracellular Ca 2+ concentration. Furthermore, activation of protein kinase C (PKC) increased concomitantly with a decrease in calponin expression. These results indicate that the isolated cells had biological activity. Our method of isolating PVSMCs from rat leads to isolation of cultured cells with activity and high purity. The approach will be useful in research studies on placental vascular diseases.

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Different protein kinase C isoenzymes mediate inhibition of cardiac rapidly activating delayed rectifier K⁺ current by different G‐protein coupled receptors

Abstract: Our results indicated that inhibition of I by activation of α -adrenoreceptors or AT receptors were mediated by PKCα and PKCε isoforms respectively, through different molecular mechanisms.

Cited by 13 publications

References 41 publications

Differential Regulation of Human Ether-à-Go-Go–Related Gene (hERG) Current and Expression by Activation of Protein Kinase C

Differential Regulation of Human Ether-à-Go-Go–Related Gene (hERG) Current and Expression by Activation of Protein Kinase C

Evidence for metabotropic function of epithelial nicotinic cholinergic receptors in rat colon

Isolation and culture of vascular smooth muscle cells from rat placenta

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Different protein kinase C isoenzymes mediate inhibition of cardiac rapidly activating delayed rectifier K+ current by different G‐protein coupled receptors

Abstract: Our results indicated that inhibition of I by activation of α -adrenoreceptors or AT receptors were mediated by PKCα and PKCε isoforms respectively, through different molecular mechanisms.

Cited by 13 publications

References 41 publications

Differential Regulation of Human Ether-à-Go-Go–Related Gene (hERG) Current and Expression by Activation of Protein Kinase C

Differential Regulation of Human Ether-à-Go-Go–Related Gene (hERG) Current and Expression by Activation of Protein Kinase C

Evidence for metabotropic function of epithelial nicotinic cholinergic receptors in rat colon

Isolation and culture of vascular smooth muscle cells from rat placenta

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Product

Resources

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Different protein kinase C isoenzymes mediate inhibition of cardiac rapidly activating delayed rectifier K⁺ current by different G‐protein coupled receptors