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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)122-134
Number of pages13
JournalCardiovascular Research
Volume62
Issue number1
DOIs
StatePublished - Apr 1 2004

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Adrenergic Agonists
Sarcoplasmic Reticulum
Calsequestrin
Ryanodine Receptor Calcium Release Channel
Caffeine
Excitation Contraction Coupling
Left Ventricular Function
Catheterization
Adrenergic Receptors
Transgenic Mice
Population
Echocardiography
triadin
Proteins
Phosphotransferases
Phosphorylation

Keywords

  • BAPTA
  • 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

Cite this

Transgenic triadin 1 overexpression alters SR Ca2+ handling and leads to a blunted contractile response to β-adrenergic agonists. / Kirchhefer, Uwe; Jones, Larry; Begrow, Frank; Boknik, Peter; Hein, Lutz; Lohse, Martin J.; Riemann, Burkhard; Schmitz, Wilhelm; Stypmann, Jörg; Neumann, Joachim.

In: Cardiovascular Research, Vol. 62, No. 1, 01.04.2004, p. 122-134.

Research output: Contribution to journalArticle

Kirchhefer, U, Jones, L, Begrow, F, Boknik, P, Hein, L, Lohse, MJ, Riemann, B, Schmitz, W, Stypmann, J & Neumann, J 2004, 'Transgenic triadin 1 overexpression alters SR Ca2+ handling and leads to a blunted contractile response to β-adrenergic agonists', Cardiovascular Research, vol. 62, no. 1, pp. 122-134. https://doi.org/10.1016/j.cardiores.2004.01.005
Kirchhefer, Uwe ; Jones, Larry ; Begrow, Frank ; Boknik, Peter ; Hein, Lutz ; Lohse, Martin J. ; Riemann, Burkhard ; Schmitz, Wilhelm ; Stypmann, Jörg ; Neumann, Joachim. / Transgenic triadin 1 overexpression alters SR Ca2+ handling and leads to a blunted contractile response to β-adrenergic agonists. In: Cardiovascular Research. 2004 ; Vol. 62, No. 1. pp. 122-134.
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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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AU - Boknik, Peter

AU - Hein, Lutz

AU - Lohse, Martin J.

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AB - 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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