Hyperphosphorylation of RyRs underlies triggered activity in transgenic rabbit model of LQT2 syndrome.

Content Provider	Semantic Scholar
Author	Terentyev, Dmitry Rees, Colin M. Li, Weiyan Cooper, Leroy L. Jindal, Hitesh K. Peng, Xuwen Lu, Yichun Terentyeva, Radmila Odening, Katja E. Daley, Jean M. Bist, K. Choi, Bum-Rak Karma, Alain Koren, Gideon
Copyright Year	2014
Abstract	RATIONALE Loss-of-function mutations in human ether go-go (HERG) potassium channels underlie long QT syndrome type 2 (LQT2) and are associated with fatal ventricular tachyarrhythmia. Previously, most studies focused on plasma membrane-related pathways involved in arrhythmogenesis in long QT syndrome, whereas proarrhythmic changes in intracellular Ca(2+) handling remained unexplored. OBJECTIVE We investigated the remodeling of Ca(2+) homeostasis in ventricular cardiomyocytes derived from transgenic rabbit model of LQT2 to determine whether these changes contribute to triggered activity in the form of early after depolarizations (EADs). METHODS AND RESULTS Confocal Ca(2+) imaging revealed decrease in amplitude of Ca(2+) transients and sarcoplasmic reticulum Ca(2+) content in LQT2 myocytes. Experiments using sarcoplasmic reticulum-entrapped Ca(2+) indicator demonstrated enhanced ryanodine receptor (RyR)-mediated sarcoplasmic reticulum Ca(2+) leak in LQT2 cells. Western blot analyses showed increased phosphorylation of RyR in LQT2 myocytes versus controls. Coimmunoprecipitation experiments demonstrated loss of protein phosphatases type 1 and type 2 from the RyR complex. Stimulation of LQT2 cells with β-adrenergic agonist isoproterenol resulted in prolongation of the plateau of action potentials accompanied by aberrant Ca(2+) releases and EADs, which were abolished by inhibition of Ca(2+)/calmodulin-dependent protein kinase type 2. Computer simulations showed that late aberrant Ca(2+) releases caused by RyR hyperactivity promote EADs and underlie the enhanced triggered activity through increased forward mode of Na(+)/Ca(2+) exchanger type 1. CONCLUSIONS Hyperactive, hyperphosphorylated RyRs because of reduced local phosphatase activity enhance triggered activity in LQT2 syndrome. EADs are promoted by aberrant RyR-mediated Ca(2+) releases that are present despite a reduction of sarcoplasmic reticulum content. Those releases increase forward mode Na(+)/Ca(2+) exchanger type 1, thereby slowing repolarization and enabling L-type Ca(2+) current reactivation.
Starting Page	786
Ending Page	792
Page Count	7
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://circresaha.smart01.highwire.org/content/circresaha/115/11/919.full.pdf?download=true
Alternate Webpage(s)	http://circres.ahajournals.org/content/circresaha/115/11/919.full.pdf?download=true
Alternate Webpage(s)	http://circres.ahajournals.org/content/circresaha/early/2014/09/23/CIRCRESAHA.115.305146.full.pdf?download=true
PubMed reference number	25249569v1
Alternate Webpage(s)	https://doi.org/10.1161/CIRCRESAHA.115.305146
DOI	10.1161/circresaha.115.305146
Journal	Circulation research
Volume Number	115
Issue Number	11
Language	English
Access Restriction	Open
Subject Keyword	Action Potentials Etherum, ether, Homeopathic preparation Handling (Psychology) Hippocampus (Brain) Hyperactive behavior Isoproterenol Long QT Syndrome Muscle Cells Mutation Myocytes, Cardiac Phosphoric Monoester Hydrolases Plasma membrane Potassium Channel Protein Kinases Protein phosphatase RYR1 gene Ryanodine Receptor Calcium Release Channel Sarcoplasmic Reticulum Tachycardia, Ventricular Western Blotting Wolff-Parkinson-White Syndrome ryanodine receptor complex location
Content Type	Text
Resource Type	Article