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.


CONCLUSIONS
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.
Kirchhefer
Uwe
U
Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Domagkstr. 12, 48149 Münster, Germany. kirchhef@uni-muenster.de
Jones
Larry R
LR
Begrow
Frank
F
Boknik
Peter
P
Hein
Lutz
L
Lohse
Martin J
MJ
Riemann
Burkhard
B
Schmitz
Wilhelm
W
Stypmann
Jörg
J
Neumann
Joachim
J
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002110:Caffeine; D002118:Calcium / Q000032:analysis / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D004594:Electrophysiology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects*; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C498270:Trdn protein, mouse; C070048:triadin; D002110:Caffeine; D002118:Calcium