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Ankyrin-based targeting pathway regulates human sinoatrial node automaticity.
Channels ( IF 3.3 ) Pub Date : 2008-12-23 , DOI: 10.4161/chan.2.6.7220
Thomas J Hund 1 , Peter J Mohler
Affiliation  

Cellular defects in ankyrin-based ion channels and transporter targeting pathways have previously been linked with abnormal vertebrate physiology and human disease. In a recent study, our group linked dysfunction in cardiac ankyrin-B function with human sinus node disease. Ankyrin-B deficient mice displayed bradycardia and heart rate variability similar to individuals harboring an ANK2 variant. Isolated sinoatrial node (SAN) cells from ankyrin-B-deficient animals displayed abnormal membrane expression of Na+/Ca2+ exchanger (NCX1), Na+/K+ ATPase (NKA), IP3 receptor (IP3R) and, surprisingly, Ca(V)1.3. Loss of ankyrin-B promoted slow and irregular Ca2+ release, as well as afterdepolarizations in isolated SAN cardiomyocytes. Our findings suggest that ankyrin-B serves as a critical focal point for channels and transporters important for sarcoplasmic reticulum (SR) calcium homeostasis as well as membrane depolarization in SAN cells. The severity and penetrance of human ANK2 sinus node dysfunction likely reflects the essential role of ankyrin-B for orchestrating membrane function of multiple SAN ion channel and transporters within a single functional pathway. Therefore, ankyrin-based pathways may serve as ideal therapeutic targets in SAN cardiomyocytes where a "multi-hit" approach is necessary to impact a complex process such as SAN cell automaticity. In summary, our new findings define a novel genetic basis for human SND and expand our understanding of the critical role that ankyrin-based targeting pathways play in excitable cell physiology.

中文翻译:

基于锚蛋白的靶向途径可调节人类窦房结的自动化程度。

基于锚蛋白的离子通道和转运蛋白靶向途径中的细胞缺陷先前与异常的脊椎动物生理学和人类疾病有关。在最近的研究中,我们的研究组将心脏锚蛋白B功能障碍与人类窦房结疾病联系起来。缺乏锚蛋白B的小鼠表现出心动过缓和心率变异性,类似于具有ANK2变异的个体。从锚蛋白B缺陷动物中分离出的窦房结(SAN)细胞显示Na + / Ca2 +交换子(NCX1),Na + / K + ATPase(NKA),IP3受体(IP3R)和令人惊讶的Ca(V)1.3的异常膜表达。锚蛋白B的丢失会促进缓慢和不规则的Ca2 +释放,以及分离的SAN心肌细胞中的去极化作用。我们的发现表明,锚蛋白B作为通道和转运蛋白的关键焦点,对于肌浆网(SR)钙稳态以及SAN细胞膜去极化非常重要。人ANK2窦房结功能障碍的严重程度和渗透率可能反映了锚蛋白B在协调单个功能途径中多个SAN离子通道和转运蛋白的膜功能方面的重要作用。因此,基于锚蛋白的途径可以作为SAN心肌细胞中理想的治疗靶标,其中“多重打击”方法对于影响诸如SAN细胞自动化等复杂过程是必需的。总而言之,我们的新发现为人类SND定义了新的遗传基础,并扩展了我们对基于锚蛋白的靶向途径在可激发细胞生理学中发挥关键作用的理解。
更新日期:2019-11-01
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