title: Transgenic triadin 1 overexpression alters SR Ca2+ handling and leads to a blunted contractile response to beta-adrenergic agonists.
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 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.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Domagkstr. 12, 48149 Münster, Germany. kirchhef@uni-muenster.de
authors.forename: Uwe
authors.initials: U
authors.lastname: Kirchhefer
authors.forename: Larry R
authors.initials: LR
authors.lastname: Jones
authors.forename: Frank
authors.initials: F
authors.lastname: Begrow
authors.forename: Peter
authors.initials: P
authors.lastname: Boknik
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: Burkhard
authors.initials: B
authors.lastname: Riemann
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Neumann
mesh_terms: 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*
chemical_list: 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