On the role of junctin in cardiac Ca2+ handling, contractility, and heart failure.
Junctin is a transmembrane protein located at the cardiac junctional sarcoplasmic reticulum (SR) and forms a quaternary complex with the Ca(2+) release channel, triadin and calsequestrin. Impaired protein interactions within this complex may alter the Ca(2+) sensitivity of the Ca(2+) release channel and may lead to cardiac dysfunction, including hypertrophy, depressed contractility, and abnormal Ca(2+) transients. To study the expression of junctin and, for comparison, triadin, in heart failure, we measured the levels of these proteins in SR from normal and failing human hearts. Junctin was below our level of detection in SR membranes from failing human hearts, and triadin was downregulated by 22%. To better understand the role of junctin in the regulation of Ca(2+) homeostasis and contraction of cardiac myocytes, we used an adenoviral approach to overexpress junctin in isolated rat cardiac myocytes. A recombinant adenovirus encoding the green fluorescent protein served as a control. Infection of myocytes with the junctin-expressing virus resulted in an increased RNA and protein expression of junctin. Ca(2+) transients showed a decreased maximum Ca(2+) amplitude, and contractility of myocytes was depressed. Our results demonstrate that an increased expression of junctin is associated with an impaired Ca(2+) homeostasis. Downregulation of junctin in human heart failure may thus be a compensatory mechanism.
Gergs
Ulrich
U
Institut für Pharmakologie und Toxikologie, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Strasse 4, 06112 Halle/Saale, Germany. ulrich.gergs@medizin.uni-halle.de
Berndt
Tobias
T
Buskase
Jan
J
Jones
Larry R
LR
Kirchhefer
Uwe
U
Müller
Frank U
FU
Schlüter
Klaus-Dieter
KD
Schmitz
Wilhelm
W
Neumann
Joachim
J
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002303:Cardiac Output, Low / Q000503:physiopathology*; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D006899:Mixed Function Oxygenases; C419389:ASPH protein, human; D002118:Calcium