Overexpression of junctin causes adaptive changes in cardiac myocyte Ca2+ signaling

被引:31
作者
Kirchhefer, U
Hanske, G
Jones, LR
Justus, I
Kaestner, L
Lipp, P
Schmitz, W
Neumann, J
机构
[1] Univ Munster, Inst Pharmakol & Toxikol, D-48149 Munster, Germany
[2] Indiana Univ, Sch Med, Dept Med, Krannert Inst Cardiol, Indianapolis, IN 46202 USA
[3] Univ Saarland, Inst Mol Zellbiol, D-66421 Homburg, Germany
[4] Univ Halle Wittenberg, Inst Pharmakol & Toxikol, D-06112 Halle, Germany
关键词
Ca2+ release units; junctional sarcoplasmic reticulum; Ca2+ handling; excitation-contraction coupling; Ca2+ sparks; cardiac function; transgenic mouse model;
D O I
10.1016/j.ceca.2005.10.004
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
In cardiac muscle, junctin forms a quaternary protein complex with the ryanodine receptor (RyR), calsequestrin, and triadin 1 at the luminal face of the junctional sarcoplasmic reticulum (jSR). By binding directly the RyR and calsequestrin, junctin may mediate the Ca2+-dependent regulatory interactions between both proteins. To gain more insight into the underlying mechanisms of impaired contractile relaxation in transgenic mice with cardiac-specific overexpression of junctin (TG), we studied cellular Ca2+ handling in these mice. We found that the SR Ca2+ load was reduced by 22% in cardiomyocytes from TG mice. Consistent with this, the frequency of Ca2+ sparks was diminished by 32%. The decay of spontaneous Ca2+ sparks was prolonged by 117% in TG. This finding was associated with a lower Na+-Ca2+ exchanger (NCX) protein expression (by 67%) and a higher basal RyR phosphorylation at Ser(2809) (by 64%) in TG. The shortening- and Delta[Ca](i) -frequency relationships (0.5-4 Hz) were flat in TG compared to wild-type (WT) which exhibited a positive staircase for both parameters. Furthermore, increasing stimulation frequencies hastened the time of relaxation and the decay of [Ca]i by a higher percentage in TG. We conclude that the impaired relaxation in TG may result from a reduced NCX expression and/or a higher SR Ca2+ leak. The altered shortening-frequency relationship in TG seems to be a consequence of an impaired excitation-contraction coupling with depressed SR Ca2+ release at higher rates of stimulation. Our data suggest that the more prominent frequency-dependent hastening of relaxation in TG results from a stimulation of SR Ca2+ transport reflected by corresponding changes of [Ca](i). (C) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:131 / 142
页数:12
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