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

  1. Uwe Kirchhefer*,a,
  2. Larry R Jonesb,
  3. Frank Begrowa,
  4. Peter Boknika,
  5. Lutz Heinc,
  6. Martin J Lohsec,
  7. Burkhard Riemannd,
  8. Wilhelm Schmitza,
  9. Jörg Stypmanne and
  10. Joachim Neumanna
  1. aInstitut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Domagkstr. 12, 48149 Münster, Germany
  2. bDepartment of Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
  3. cInstitut für Pharmakologie, Universität Würzburg, 97078 Würzburg, Germany
  4. dKlinik und Poliklinik für Nuklearmedizin, Westfälische Wilhelms-Universität, 48149 Münster, Germany
  5. eMedizinische Klinik und Poliklinik C, Westfälische Wilhelms-Universität, 48149 Münster, Germany
  1. *Corresponding author. Tel.: +49-251-8355510; fax: +49-251-8355501. Email address: kirchhef{at}uni-muenster.de
  • Received April 23, 2003.
  • Revision received December 12, 2003.
  • Accepted January 2, 2004.

Abstract

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.

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Key words

  • Abbreviations:
    Abbreviations
    EGTA
    ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
    HEPES
    N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]
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  1. Cardiovasc Res (2004) 62 (1): 122-134. doi: 10.1016/j.cardiores.2004.01.005
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