Zhang Tong, Miyamoto Shigeki, Brown Joan Heller
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.
Recent Prog Horm Res. 2004;59:141-68. doi: 10.1210/rp.59.1.141.
Calcium (Ca(2+)) is a critical second messenger in cell signaling. Elevated intracellular Ca(2+) can activate numerous Ca(2+)-regulated enzymes. These enzymes have different subcellular localizations and may respond to distinct modes of Ca(2+) mobilization. In cardiac muscle, Ca(2+) plays a central role in regulating contractility, gene expression, hypertrophy, and apoptosis. Many cellular responses to Ca(2+) signals are mediated by Ca(2+)/calmodulin-dependent enzymes, among which is the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Putative substrates for CaMKII include proteins involved in regulating Ca(2+) storage and release, transcription factors, and ion channels. The major isoform of CaMKII in the heart is CaMKIIdelta. Two cardiac splice variants, CaMKIIdelta(B) and delta(C), differ in whether they contain a nuclear localization sequence. Our laboratory has examined the hypothesis that the nuclear delta(B) and the cytoplasmic delta(C) isoforms respond to different Ca(2+) stimuli and have distinct effects on hypertrophic cardiac growth and Ca(2+) handling. We have shown that pressure overload-induced hypertrophy differentially affects the nuclear delta(B) and the cytoplasmic delta(C) isoforms of CaMKII. Additionally, using isolated myocytes and transgenic mouse models, we demonstrated that the nuclear CaMKIIdelta(B) isoform plays a key role in cardiac gene expression associated with cardiac hypertrophy. The cytoplasmic CaMKIIdelta(C) isoform phosphorylates substrates involved in Ca(2+) handling. Dysregulation of intracellular Ca(2+) and resulting changes in excitation-contraction coupling characterize heart failure and can be induced by in vivo overexpression of CaMKIIdelta(C) and phosphorylation of its substrates. The differential location of CaMKII isoforms and their relative activation by physiological vs. pathological stimuli may provide a paradigm for exploring and elucidating how Ca(2+)/CaMKII pathways can serve as both friends and foes in the heart.
钙（Ca(2+)）是细胞信号传导中的关键第二信使。细胞内Ca(2+)升高可激活众多受Ca(2+)调节的酶。这些酶具有不同的亚细胞定位，可能对不同的Ca(2+)动员模式做出反应。在心肌中，Ca(2+)在调节收缩性、基因表达、肥大和凋亡方面发挥着核心作用。许多细胞对Ca(2+)信号的反应是由Ca(2+)/钙调蛋白依赖性酶介导的，其中包括Ca(2+)/钙调蛋白依赖性蛋白激酶II（CaMKII）。CaMKII的推定底物包括参与调节Ca(2+)储存和释放的蛋白质、转录因子和离子通道。心脏中CaMKII的主要亚型是CaMKIIdelta。两种心脏剪接变体CaMKIIdelta(B)和delta(C)在是否含有核定位序列方面存在差异。我们实验室研究了以下假设：核delta(B)和细胞质delta(C)亚型对不同的Ca(2+)刺激做出反应，并对肥厚性心脏生长和Ca(2+)处理具有不同的影响。我们已经表明，压力超负荷诱导的肥大对CaMKII的核delta(B)和细胞质delta(C)亚型有不同的影响。此外，使用分离的心肌细胞和转基因小鼠模型，我们证明核CaMKIIdelta(B)亚型在与心脏肥大相关的心脏基因表达中起关键作用。细胞质CaMKIIdelta(C)亚型使参与Ca(2+)处理的底物磷酸化。细胞内Ca(2+)失调以及由此导致的兴奋-收缩偶联变化是心力衰竭的特征，并且可由CaMKIIdelta(C)的体内过表达及其底物的磷酸化诱导。CaMKII亚型的不同定位及其在生理与病理刺激下的相对激活可能为探索和阐明Ca(2+)/CaMKII途径如何在心脏中既有益又有害提供一个范例。
