Severs N J
National Heart and Lung Institute, University of London, England.
Histol Histopathol. 1995 Apr;10(2):481-501.
Electrical coupling between cardiac muscle cells is mediated by specialised sites of plasma membrane interaction termed gap junctions, one of three types of intercellular junction of the cardiac intercalated disk. Gap junctions consist of clusters of plasma membrane channels directly linking the cytoplasmic compartments of neighbouring cells. Gap-junctional channels are constructed from connexins, a multigene family of conserved proteins. The principal connexin isoform of the mammalian heart is connexin43; other connexins, notably connexin40, connexin45 and connexin37, are also expressed but in smaller quantities. Antibodies directed against unique sequences of these molecules allow investigation of the role of gap junctions and their component connexins in relation to the electrophysiological properties of the healthy and diseased heart. Confocal laser scanning microscopy of working ventricular myocytes immunolabelled with anticonnexin43 antibodies permits highly sensitive detection of gap junctions, allowing detailed analysis of the spatial distribution of the conduction pathways from the level of the cell to that of the tissue as a whole. Gap junction distribution, number and regional variations in the type of connexin expressed all contribute to the uniform anisotropic pattern of impulse spread characteristic of normal myocardium and the orderly, sequential contraction of the cardiac chambers. Connexin40 is preferentially expressed by myocytes of the atrioventricular conduction system and represents a specialisation facilitating fast conduction, allowing rapid distribution of the impulse throughout the working ventricle. Two major abnormalities in connexin43 gap junctions are detected in human ischaemic heart disease. First, at border zones adjacent to infarct scars, zones which are particularly prone to re-entry arrhythmia, there is marked disruption of the usual ordered distribution pattern of gap junctions. Second, a widespread downregulation of connexin43 gap junctions occurs in myocardium distant from the infarct, a change that is also found in the hypertrophic (non-ischaemic) heart. Consequent localised heterogeneous conduction and reduced conduction velocity provide an explanation for the genesis of re-entry arrhythmias. A current working hypothesis is that reduction in connexin43 gap junctions is a general pathogenetic feature of cardiac disease which predisposes the heart to arrhythmia, and that this reduction may form part of a wider pattern of alteration in the levels of other connexin isoforms.
心肌细胞之间的电偶联是由称为缝隙连接的特殊质膜相互作用位点介导的，缝隙连接是心脏闰盘三种细胞间连接类型之一。缝隙连接由直接连接相邻细胞质区室的质膜通道簇组成。缝隙连接通道由连接蛋白构建而成，连接蛋白是一个保守蛋白的多基因家族。哺乳动物心脏的主要连接蛋白亚型是连接蛋白43；其他连接蛋白，特别是连接蛋白40、连接蛋白45和连接蛋白37也有表达，但数量较少。针对这些分子独特序列的抗体可用于研究缝隙连接及其组成连接蛋白在健康和患病心脏电生理特性方面的作用。用抗连接蛋白43抗体进行免疫标记的工作心室肌细胞的共聚焦激光扫描显微镜检查可高度灵敏地检测缝隙连接，从而能够从细胞水平到整个组织水平详细分析传导途径的空间分布。缝隙连接的分布、数量以及所表达连接蛋白类型的区域差异，都有助于正常心肌冲动传播特征性的均匀各向异性模式以及心腔的有序、顺序收缩。连接蛋白40优先由房室传导系统的心肌细胞表达，代表一种促进快速传导的特化结构，可使冲动在整个工作心室中快速分布。在人类缺血性心脏病中检测到连接蛋白43缝隙连接的两个主要异常情况。首先，在与梗死瘢痕相邻的边界区，即特别容易发生折返性心律失常的区域，缝隙连接通常的有序分布模式明显破坏。其次，在远离梗死灶的心肌中，连接蛋白43缝隙连接广泛下调，这种变化在肥厚性（非缺血性）心脏中也有发现。由此导致的局部异质性传导和传导速度降低为折返性心律失常的发生提供了解释。目前的一个工作假设是，连接蛋白43缝隙连接的减少是心脏疾病的一个普遍发病机制特征，使心脏易患心律失常，并且这种减少可能是其他连接蛋白亚型水平更广泛改变模式的一部分。
