EphB signaling inhibits gap junctional intercellular communication and synchronized contraction in cultured cardiomyocytes
EphB signaling inhibits gap junctional intercellular communication and synchronized contraction in cultured cardiomyocytes
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DOI：
10.1007/s00395-011-0219-3
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发表时间：
2011-11-01
影响因子：
9.5
通讯作者：
Ogawa, Kazushige
中科院分区：
文献类型：
--
作者：
Ishii, Maki;Mueller, Itsuki;Ogawa, Kazushige
ephr受体和ephrin配体是膜结合的细胞-细胞通讯分子，不仅在发育中而且在许多成年器官的生理学中具有重要作用。然而，它们在心肌中的细胞定位和功能几乎是未知的，因此，我们研究了EphB受体和ephrin-B配体在啮齿动物心室中的表达及其在原代培养的啮齿动物心肌细胞中的功能。通过RT-PCR、免疫组织化学和原位杂交的检查显示，EphB受体优先表达于成年小鼠心室中的心肌细胞和脉管系统中的ephrin-B配体。有趣的是，我们发现，通过用肝配蛋白-B1-Fc刺激在啮齿动物心肌细胞的原代培养物中诱导高水平的EphB受体活化，使在治疗前同步收缩的相邻心肌细胞簇的收缩减少。免疫共沉淀实验显示EphB 4与连接蛋白43（心肌中间隙连接的主要组分）物理关联，并且EphB激活抑制心肌细胞之间的间隙连接细胞内通讯。目前的研究结果表明，ephrin-B-EphB信号可以通过对缝隙连接的影响来调节心肌细胞的电耦合。
Eph receptors and ephrin ligands are membrane-bound cell-cell communication molecules with important roles not only in development but also in the physiology of many adult organs. However, their cellular localization and functions in the myocardium are virtually unknown and therefore, we have investigated the expression of EphB receptors and ephrin-B ligands in the rodent heart ventricles and their functions in the rodent cardiomyocytes of primary culture. Examinations by RT-PCR, immunohistochemistry and in situ hybridization revealed that the EphB receptors are preferentially expressed in cardiomyocytes and ephrin-B ligands in the vasculature in adult mouse heart ventricles. Interestingly, we found that inducing high levels of EphB receptor activation in primary cultures of rodent cardiomyocytes by stimulation with ephrin-B1-Fc desynchronized the contraction of adjacent clusters of cardiomyocytes that had contracted synchronously before the treatment. Co-immunoprecipitation experiments revealed that EphB4 physically associates with connexin43, a major component of gap junctions in the myocardium, and that EphB activation inhibits gap junctional intracellular communication between cardiomyocytes. The present findings suggest that ephrin-B-EphB signaling can modulate the electrical coupling of cardiomyocytes through effects on gap junctions.