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Kirchhefer, U. et al.

Kirchhefer, Jones, Begrow, Boknik, Hein, Lohse, Riemann, Schmitz, Stypmann, Neumann,

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

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 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. 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 beta-adrenergic agonists in TG mice.[1]

References

Transgenic triadin 1 overexpression alters SR Ca2+ handling and leads to a blunted contractile response to beta-adrenergic agonists. Kirchhefer, U., Jones, L.R., Begrow, F., Boknik, P., Hein, L., Lohse, M.J., Riemann, B., Schmitz, W., Stypmann, J., Neumann, J. Cardiovasc. Res. (2004) [Pubmed]

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