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

Uwe Kirchhefer, Larry R. Jones, Frank Begrow, Peter Boknik, Lutz Hein, Martin J. Lohse, Burkhard Riemann, Wilhelm Schmitz, Jörg Stypmann, Joachim Neumann

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Objective: 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. Methods: 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. Results: 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 β-adrenergic receptor (β-AR) stimulation in TG hearts was associated with an increased protein expression of β-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 β-AR stimulation. Conclusion: 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 β-adrenergic agonists in TG mice.

Original languageEnglish (US)
Pages (from-to)122-134
Number of pages13
JournalCardiovascular research
Issue number1
StatePublished - Apr 1 2004


  • Calcium (cellular)
  • Contractile function
  • e-c Coupling
  • EGTA
  • Ethylene glycol bis(β-aminoethyl ether)-N,N,N′, N′-tetraacetic acid
  • Protein phosphorylation
  • SR (function)

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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