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http://purl.uniprot.org/citations/21700933http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/21700933http://www.w3.org/2000/01/rdf-schema#comment"

Rationale

L-type Ca(2+) (Ca(V)1.2) channels shape the cardiac action potential waveform and are essential for excitation-contraction coupling in heart. A gain-of-function G406R mutation in a cytoplasmic loop of Ca(V)1.2 channels causes long QT syndrome 8 (LQT8), a disease also known as Timothy syndrome. However, the mechanisms by which this mutation enhances Ca(V)1.2-LQT8 currents and generates lethal arrhythmias are unclear.

Objective

To test the hypothesis that the anchoring protein AKAP150 modulates Ca(V)1.2-LQT8 channel gating in ventricular myocytes.

Methods and results

Using a combination of molecular, imaging, and electrophysiological approaches, we discovered that Ca(V)1.2-LQT8 channels are abnormally coupled to AKAP150. A pathophysiological consequence of forming this aberrant ion channel-anchoring protein complex is enhanced Ca(V)1.2-LQT8 currents. This occurs through a mechanism whereby the anchoring protein functions like a subunit of Ca(V)1.2-LQT8 channels that stabilizes the open conformation and augments the probability of coordinated openings of these channels. Ablation of AKAP150 restores normal gating in Ca(V)1.2-LQT8 channels and protects the heart from arrhythmias.

Conclusion

We propose that AKAP150-dependent changes in Ca(V)1.2-LQT8 channel gating may constitute a novel general mechanism for Ca(V)1.2-driven arrhythmias."xsd:string
http://purl.uniprot.org/citations/21700933http://purl.org/dc/terms/identifier"doi:10.1161/circresaha.111.248252"xsd:string
http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/author"Scott J.D."xsd:string
http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/author"Yuan C."xsd:string
http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/author"Navedo M.F."xsd:string
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http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/author"Cheng E.P."xsd:string
http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/author"Dixon R.E."xsd:string
http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/date"2011"xsd:gYear
http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/name"Circ Res"xsd:string
http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/pages"255-261"xsd:string
http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/title"Restoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein."xsd:string
http://purl.uniprot.org/citations/21700933http://purl.uniprot.org/core/volume"109"xsd:string
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