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http://purl.uniprot.org/citations/27997898http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27997898http://www.w3.org/2000/01/rdf-schema#comment"

Background

The rapid delayed rectifier K+ current (IKr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. α1-adrenoceptors (α1-AR) activation reduces IKr but, despite the clear relationship between an increase in the sympathetic tone and arrhythmias, the mechanisms underlying the α1-AR regulation of the hERG channel are controversial. Thus, we aimed to investigate the mechanisms by which α1-AR stimulation regulates IKr.

Methods

α1-adrenoceptors, hERG channels, auxiliary subunits minK and MIRP1, the non PIP2-interacting mutant D-hERG (with a deletion of the 883-894 amino acids) in the C-terminal and the non PKC-phosphorylable mutant N-terminal truncated-hERG (NTK-hERG) were transfected in HEK293 cells. Cell membranes were extracted by centrifugation and the different proteins were visualized by Western blot. Potassium currents were recorded by the patch-clamp technique. IKr was recorded in isolated feline cardiac myocytes.

Results

Activation of the α1-AR reduces the amplitude of IhERG and IKr through a positive shift in the activation half voltage, which reduces the channel availability at physiological membrane potentials. The intracellular pathway connecting the α1-AR to the hERG channel in HEK293 cells includes activation of the Gαq protein, PLC activation and PIP2 hydrolysis, activation of PKC and direct phosphorylation of the hERG channel N-terminal. The PKC-mediated IKr channel phosphorylation and subsequent IKr reduction after α1-AR stimulation was corroborated in feline cardiac myocytes.

Conclusions

These findings clarify the link between sympathetic nervous system hyperactivity and IKr reduction, one of the best characterized causes of torsades de pointes and ventricular fibrillation."xsd:string
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http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/author"Gallego M."xsd:string
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/author"Alday A."xsd:string
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/author"Urrutia J."xsd:string
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/author"Sanchez-Chapula J.A."xsd:string
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/author"Arechiga-Figueroa I.A."xsd:string
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/author"Malagueta-Vieira L.L."xsd:string
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/name"Cell Physiol Biochem"xsd:string
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/pages"1261-1273"xsd:string
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/title"Mechanisms of IhERG/IKr Modulation by alpha1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes."xsd:string
http://purl.uniprot.org/citations/27997898http://purl.uniprot.org/core/volume"40"xsd:string
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