Study on chronic heart failure using mutant phospholamban transgenic mice

Phospholamban （PLN），一种碳水化合物多糖视网膜的整体膜蛋白，可以相对抑制Cai-D12 + Cai-D1-ATPase（SERCA），以在Cardiac Contracility和Relaxation的调节中发挥关键作用。我们研究了PLN抑制的分子机制，我们在哪些主要部位制造了转基因老鼠，高度抑制的PLN突变蛋白在与博士合作中过度表达。H..多伦多大学的麦克伦南。我们的结果正在跟进：1。PLN与SERCA的相互作用至少在两个、可能三个站点;细胞系域（域Ia）、跨膜螺旋（域II）和细胞系膜边界（域Ib）。内源性相互作用是对SERCA活动的抑制，而细胞塑性相互作用本身并不是抑制作用，这也是生理学调节效应的必要条件。我们建议通过四个基础电路通过一个长波抑制剂相互作用晚上在一系列细胞系和跨膜相互作用网站上传播PLN和SERCA相互作用。与跨膜序列（M6）的PLN跨膜域交互。The interaction site consists of four residues which form the hydrophobic face of the proposed helix on the opposite face to the CaイイD12+イエD1 binding site。由于M&被定位在一个浅坡口中，关键的替代方案是形成提议的交互站点面对的Lipid Billayer，这是可以做到的，因为该坡口可以提供PLN跨膜螺旋并访问交互站点。Transgenic Mice过度表达单体，主导作用，高抑制物PLN突变体产生。他们展示了不受影响的心脏病收缩和放松。

Phospholamban (PLN), an integral membrane protein of cardiac sarcoplasmic reticulum, reversibly inhibits the CaィイD12+ィエD1-ATPase (SERCA) to play a pivotal role in the regulation of cardiac contractility and relaxation. We examined the molecular mechanism of SERCA inhibition by PLN and we have created transgenic mice in which the dominant, highly inhibitory PLN mutant proteins are overexpressed in collaboration with Dr. D. H. MacLennan of the University of Toronto. Our results are following :1. PLN interacts with SERCA through at least two, possibly three sites ; cytoplasmic domain (domain Ia), transmembrane helix (domain II), and cytoplasmic-membrane boundary (domain Ib). Intramembrane interactions are inhibitory on SERCA activity, while the cytoplasmic interactions are not inhibitory itself although it is essential for the physiological regulatory effect. We propose that PLN and SERCA interact via a four base circuit through which long range inhibitory interactions night be propagated among a series of cytoplasmic and transmembrane interaction sites.2. PLN transmembrane domain interacts with the transmembrane sequence (M6) of SERCA. The interaction site consists of four residues which form the hydrophobic face of the proposed helix on the opposite face to the CaィイD12+ィエD1 binding site. As M& is located in a shallow groove with the key residues which form the proposed interaction site facing the lipid bilayer, it is conceivable that the groove may provide the PLN transmembrane helix with access to the interaction site.3. Transgenic mice overexpressing monomeric, dominant-acting, highly inhibitory PLN mutants were generated. They exhibited impaired cardiac contractility and relaxation.