Transgenic triadin 1 overexpression alters SR Ca2+ handling and leads to a blunted contractile response to β-adrenergic agonists

• Published in: Cardiovascular research 2004-04, Vol.62 (1), p.122-134
• Main Authors: KIRCHHEFER, Uwe, JONES, Larry R, BEGROW, Frank, BOKNIK, Peter, HEIN, Lutz, LOHSE, Martin J, RIEMANN, Burkhard, SCHMITZ, Wilhelm, STYPMANN, Jörg, NEUMANN, Joachim
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - pharmacology; Animals; Biological and medical sciences; Caffeine; Calcium - analysis; Calcium - metabolism; Cardiology. Vascular system; Carrier Proteins - genetics; Carrier Proteins - metabolism; Echocardiography, Doppler; Electrocardiography; Electrophysiology; Medical sciences; Mice; Mice, Transgenic; Microscopy, Confocal; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocardial Contraction - drug effects; Phosphorylation; Sarcoplasmic Reticulum - metabolism
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/j.cardiores.2004.01.005

Ca2+ release from the cardiac junctional sarcoplasmic reticulum (SR) is regulated by a complex of proteins, including the ryanodine receptor (RyR), calsequestrin (CSQ), junctin (JCN), and triadin 1 (TRD). Moreover, triadin 1 appears to anchor calsequestrin to the ryanodine receptor. To determine whether triadin 1 overexpression alters excitation-contraction coupling, we examined the effects of cardiac-specific overexpression of triadin 1 on SR Ca2+ handling and contractility in transgenic (TG) compared to wild-type (WT) mice. The overexpression of triadin 1 was associated with an enhanced SR Ca2+ load, reflected by a 22% higher amplitude of caffeine-induced Ca2+ transients. The decline of Ca2+ transients during caffeine exposure was prolonged by 57%. The detection of resting spontaneous SR Ca2+ release events (Ca2+ sparks) revealed an increased amplitude (by 16%), decline (by 47%), and width (by 47%) in TG. This was associated with a redistribution of Ca2+ spark amplitudes from one population to two populations. Measurement of cardiac function by echocardiography and left ventricular (LV) catheterization revealed a decreased cardiac contractility in vivo. The impaired response to beta-adrenergic receptor (beta-AR) stimulation in TG hearts was associated with an increased protein expression of beta-AR kinase 1. In addition, the increase of the L-type Ca2+ peak current and the increase of phospholamban (PLB) phosphorylation at Thr17 were reduced under beta-AR stimulation. Taken together, our data suggest that triadin 1 overexpression results in a complex modulation of SR Ca2+ handling, which may contribute, at least in part, to the depressed basal contractility and the blunted response to beta-adrenergic agonists in TG mice.