© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Impaired relaxation in transgenic mice overexpressing junctin
aInstitut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Domagkstraße 12, 48149 Münster, Germany
bDepartment of Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
cMedizinische Klinik B und Zentrale Projektgruppe Ultrastrukturforschung am Gerhard-Domagk-Institut für Pathologie, Westfälische Wilhelms-Universität, 48149 Münster, Germany
dMedizinische Klinik und Poliklinik C, Westfälische Wilhelms-Universität, 48149 Münster, Germany
eKlinik und Poliklinik für Nuklearmedizin, Westfälische Wilhelms-Universität, 48149 Münster, Germany
fDepartment of Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
* Corresponding author. Tel.: +49-251-835-5510; fax: +49-251-835-5501. kirchhef{at}uni-muenster.de
Objective: Junctin is a major transmembrane protein in cardiac junctional sarcoplasmic reticulum, which forms a quaternary complex with the ryanodine receptor (Ca2+ release channel), triadin, and calsequestrin. Methods: To better understand the role of junctin in excitation–contraction coupling in the heart, we generated transgenic mice with targeted overexpression of junctin to mouse heart, using the 
-MHC promoter to drive protein expression. Results: The protein was overexpressed 10-fold in mouse ventricles and overexpression was accompanied by cardiac hypertrophy (19%). The levels of two other junctional SR-proteins, the ryanodine receptor and triadin, were reduced by 32% and 23%, respectively. However, [3H]ryanodine binding and the expression levels of calsequestrin, phospholamban and SERCA2a remained unchanged. Cardiomyocytes from junctin-overexpressing mice exhibited impaired relaxation: Ca2+ transients decayed at a slower rate and cell relengthening was prolonged. Isolated electrically stimulated papillary muscles from junctin-overexpressing hearts exhibited prolonged mechanical relaxation, and echocardiographic parameters of relaxation were prolonged in the living transgenic mice. The amplitude of caffeine-induced Ca2+ transients was lower in cardiomyocytes from junctin-overexpressing mice. The inactivation kinetics of L-type Ca2+ channel were prolonged in junctin-overexpressing cardiomyocytes using Ca2+ or Ba2+ as charge carriers. Conclusion: Our data provide evidence that cardiac-specific overexpression of junctin is accompanied by impaired myocardial relaxation with prolonged Ca2+ transient kinetics on the cardiomyocyte level.
KEYWORDS bp, base pairs; EGTA, ethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid; HEPES, (N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]); PAGE, polyacrylamide gel electrophoresis; SDS, sodium n-dodecyl sulphate; SR, sarcoplasmic reticulum
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