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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/H3165    most recent 00799.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kirchhefer, U. Articles by Neumann, J. Search for Related Content PubMed PubMed Citation Articles by Kirchhefer, U. Articles by Neumann, J.

Triadin is a critical determinant of cellular Ca cycling and contractility in the heart

¹Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Münster, Germany; ²Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic; ³Institut für Pathologie und Neuropathologie, Universitätsklinikum Essen, Essen; ⁴Gerhard-Domagk-Institut für Pathologie and ⁵Medizinische Klinik und Poliklinik C, Universitätsklinikum Münster, Münster; and ⁶Institut für Pharmakologie und Toxikologie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany

Submitted 10 July 2007 ; accepted in final form 17 September 2007

Triadin is involved in the regulation of cardiac excitation-contraction coupling. However, the extent of its contribution to the regulation of sarcoplasmic reticulum (SR) Ca release remains unclear, because overexpression of triadin in single-transgenic mice was associated with the downregulation of its homologous protein, junctin. In the present study, this problem was circumvented by cross-breeding of mice with heart-directed overexpression of triadin and junctin (JxT). This resulted in a stable approximately threefold expression of total triadin but unchanged junctin protein. Transgenic mice exhibited cardiac hypertrophy and structural abnormalities of myofibrils. Measurement of cardiac function by echocardiography and edge detection in myocytes revealed an impaired relaxation in JxT mice. The stimulation of -adrenergic receptors resulted in a depressed contractility and an impaired relaxation in catheterized hearts and myocytes of JxT mice. The use of a maximum stimulation frequency (5 Hz) was associated with both a lower shortening and relengthening in isolated myocytes of JxT mice. The contractile effects in JxT myocytes were paralleled by similar changes of the intracellular Ca concentration ([Ca]_i) peak amplitude and Ca transient decay kinetics at basal conditions, under administration of isoproterenol, and with high-frequency stimulation. Finally, we found a higher caffeine-induced [Ca]_i peak amplitude in JxT myocytes. Our data show that the stable expression of triadin, independent of junctin expression, resulted in cardiac hypertrophy, prolonged basal relaxation, a depressed response to -adrenergic agonists, and altered Ca transients. Thus the maintenance of triadin expression is essential for normal SR Ca cycling and contractile function.

transgenic mice; sarcoplasmic reticulum; hypertrophy; Ca signaling; cardiac function; force-frequency relationship; -adrenergic receptor stimulation