title: Modulation of SR Ca2+ release by the triadin-to-calsequestrin ratio in ventricular myocytes.
abstract: Calsequestrin (CSQ) is a Ca(2+) storage protein that interacts with triadin (TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular tetrameric Ca(2+) signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice (TG(CSQ)) was associated with heart failure, attenuation of SR Ca(2+) release, and downregulation of associated junctional SR proteins, e.g., TRN. Hence, we tested whether co-overexpression of CSQ and TRN in mouse hearts (TG(CxT)) could be beneficial for impaired intracellular Ca(2+) signaling and contractile function. Indeed, the depressed intracellular Ca(2+) concentration ([Ca](i)) peak amplitude in TG(CSQ) was normalized by co-overexpression in TG(CxT) myocytes. This effect was associated with changes in the expression of cardiac Ca(2+) regulatory proteins. For example, the protein level of the L-type Ca(2+) channel Ca(v)1.2 was higher in TG(CxT) compared with TG(CSQ). Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) expression was reduced in TG(CxT) compared with TG(CSQ), whereas JUN expression and [(3)H]ryanodine binding were lower in both TG(CxT) and TG(CSQ) compared with wild-type hearts. As a result of these expressional changes, the SR Ca(2+) load was higher in both TG(CxT) and TG(CSQ) myocytes. In contrast to the improved cellular Ca(2+), transient co-overexpression of CSQ and TRN resulted in a reduced survival rate, an increased cardiac fibrosis, and a decreased basal contractility in catheterized mice, working heart preparations, and isolated myocytes. Echocardiographic and hemodynamic measurements revealed a depressed cardiac performance after isoproterenol application in TG(CxT) compared with TG(CSQ). Our results suggest that co-overexpression of CSQ and TRN led to a normalization of the SR Ca(2+) release compared with TG(CSQ) mice but a depressed contractile function and survival rate probably due to cardiac fibrosis, a lower SERCA2a expression, and a blunted response to β-adrenergic stimulation. Thus the TRN-to-CSQ ratio is a critical modulator of the SR Ca(2+) signaling.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Münster, Germany. kucerova@uni-muenster.de
authors.forename: Dana
authors.initials: D
authors.lastname: Kučerová
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Peter
authors.initials: P
authors.lastname: Bokník
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Alexander
authors.initials: A
authors.lastname: Heinick
authors.forename: Marek
authors.initials: M
authors.lastname: Mát'uš
authors.forename: Frank U
authors.initials: FU
authors.lastname: Müller
authors.forename: Joachim
authors.initials: J
authors.lastname: Neumann
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
authors.forename: Uwe
authors.initials: U
authors.lastname: Kirchhefer
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D002155:Calsequestrin; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C498270:Trdn protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium