Structure-activity relations of the cardiac gap junction channel.
Structure-activity relations of the cardiac gap junction channel.
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心脏间隙连接通道的结构-活动关系。
DOI：
10.1152/ajpcell.1990.258.2.c195
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发表时间：
1990
期刊：
影响因子：
--
通讯作者：
Burt,JM
中科院分区：
文献类型：
--
作者：
Spray,DC;Burt,JM
心脏缝隙连接通道在同步起搏细胞和允许脉冲沿着传导系统和整个心室肌传播中起重要作用。这些通道，支持电流在纵向和横向方向上流动，是可渗透的阴离子和阳离子半径小于约0.5 nm，并在大鼠心脏的单位电导的顺序为50 pS。这种单一的电导与通道的几何形状是一致的，通道的几何形状是由直径足够大的圆柱形孔描述的，以使明亮的荧光染料分子荧光黄在细胞之间通过。这些通道和生物系统中的其他通道一样，通过各种处理打开和关闭，这一过程称为门控。细胞质酸化降低连接电导（gj），这是一种明显增强的肌浆钙离子升高的效果。减少gj也发生在各种亲脂性分子的反应中，包括氟烷、庚醇和不饱和脂肪酸;作用机制可能涉及差距连接通道的蛋白质-脂质微环境的破坏。花生四烯酸解偶联，这种作用被脂氧合酶代谢途径的抑制剂部分但不完全阻断。环氧合酶抑制剂没有保护作用。某些环核苷酸可以快速增加gj [腺苷3 '，5'-环一磷酸（cAMP）]或略微降低它[鸟苷3 '，5'-环一磷酸（cGMP）]，使用这些环核苷酸作为第二信使的药物（分别为异丙肾上腺素和卡巴胆碱）产生一致的效果。预期引起蛋白激酶C活化的药物（促肿瘤的佛波酯和甘油二酯）迅速增加gj。从大鼠心脏组织中克隆了差距连接蛋白基因。从蛋白质的一级序列中，提出了这些治疗方法中的每一种治疗方法在推定的细胞质结构域内的可能作用位点。响应于关闭通道的门控刺激（氟烷、CO2、庚醇），单一通道电导不变，表明这些药剂通过减少开放时间概率起作用。总之，这些特性构成了我们奋进定义药理学试剂的开始，这些药理学试剂在心脏组织中的同步放电、传导速度和等熵波阵面传播的治疗操作中可能有用。
Cardiac gap junction channels play the important roles of synchronizing pacemaker cells and allowing impulse propagation along the conduction system and throughout the ventricular myocardium. These channels, which support current flow in both longitudinal and tranverse directions, are permeable to anions and cations with radii less than approximately 0.5 nm and in rat heart have unitary conductances on the order of 50 pS. This unitary conductance is consistent with channel geometry described by a right cylindrical pore with diameter large enough for the brilliantly fluorescent dye molecule lucifer yellow to pass between cells. These channels, like others in biological systems, are opened and closed by various treatments, a process termed gating. Cytoplasmic acidification reduces junctional conductance (gj), an effect that is apparently potentiated by elevated myoplasmic Ca ions. Reduced gj also occurs in response to a variety of lipophilic molecules, including halothane, heptanol, and unsaturated fatty acids; the mechanism of action may involve disruption of the protein-lipid microenvironment of the gap junction channel. Arachidonic acid uncouples, and this effect is partially, but incompletely, blocked by an inhibitor of the lipoxygenase metabolic pathways. Cyclooxygenase inhibitors have no protective effects. Certain cyclic nucleotides can rapidly increase gj [adenosine 3',5'-cyclic monophosphate (cAMP)] or slightly decrease it [guanosine 3',5'-cyclic monophosphate (cGMP)], and agents that use these cyclic nucleotides as second messengers (isoproterenol and perhaps carbachol, respectively) produce consistent effects. Agents expected to cause protein kinase C activation (tumor-promoting phorbol esters and diacylglycerol) increase gj rapidly. The gap junction protein from rat heart has been cloned and sequenced. From the primary sequence for the protein, plausible sites of action within the putative cytoplasmic domains are proposed for each of these treatments. In response to gating stimuli that close the channel (halothane, CO2, heptanol), unitary channel conductance is unchanged, suggesting that these agents act by reducing open time probability. Together, these properties constitute the beginnings of our endeavor to define pharmacological agents that are potentially useful in therapeutic manipulation of synchronous discharge, conduction velocity, and isochronous wavefront propagation in cardiac tissue.