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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >α_1-Adrenoceptor stimulation potentiates L-type Ca~(2+) current through Ca~(2+)/calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes
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α_1-Adrenoceptor stimulation potentiates L-type Ca~(2+) current through Ca~(2+)/calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes

机译：α_1-肾上腺素能受体刺激通过大鼠心室肌细胞中Ca〜（2 +）/钙调蛋白依赖性PK II（CaMKII）激活增强L型Ca〜（2+）电流

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摘要

α_1-Adrenoceptor stimulation (α_1ARS) modulates cardiac muscle contraction under physiological conditions by means of changes in Ca~(2+) current through L-type channels (I_(Ca,L)) and Ca~(2+) sensitivity of the myofilaments. However, the cellular mechanisms of α_1ARS are not fully clarified. In this study, we investigated the role of Ca~(2+)/calmodulin-dependent PK II (CaMKII) in the regulation of I_(Ca,L) during α_1ARS in isolated adult rat ventricular myocytes by using the perforated patch-clamp technique. CaMKII inhibition with 0.5 μM KN-93 abolished the potentiation in I_(Ca,L) observed during α_1ARS by 10 μM phenylephrine. In the presence of PKC inhibitor (10 μM chelerythrine), the potentiation of I_(Ca,L) by phenylephrine also disappeared. In Western immunoblotting analysis, phenylephrine (≥ 1 μM) increased the amount of autophosphorylated CaMKII (active CaMKII) significantly, and this increase was abolished by CaMKII inhibition or PKC inhibition. Also, we investigated changes in the subcellular localization of active CaMKII by using immuno-fluorescence microscopy and immunoelectron microscopy. Before α_1ARS, active CaMKII was exclusively located just beneath the plasmalemma. However, after α_1ARS, active CaMKII was localized close to transverse tubules, where most of L-type Ca~(2+) channels are located. From these results, we propose that CaMKII, which exists near transverse tubules, is activated and phosphorylated by α_1ARS and that CaMKII activation directly potentiates I_(Ca,L) in rat ventricular myocytes.
机译：α_1-肾上腺素能受体刺激（α_1ARS）通过改变通过L型通道（I_（Ca，L））的Ca〜（2+）电流和肌丝的Ca〜（2+）敏感性来调节生理条件下的心肌收缩。但是，α_1ARS的细胞机制尚未完全阐明。在这项研究中，我们使用穿孔膜片钳技术研究了Ca〜（2 +）/钙调蛋白依赖性PK II（CaMKII）在离体成年大鼠心室肌细胞α_1ARS期间对I_（Ca，L）的调节作用。用0.5μMKN-93抑制CaMKII消除了10μM苯肾上腺素在α_1ARS期间观察到的I_（Ca，L）增强作用。在PKC抑制剂（10μM白屈菜红碱）存在下，去氧肾上腺素对I_（Ca，L）的增强作用也消失了。在Western免疫印迹分析中，去氧肾上腺素（≥1μM）显着增加了自磷酸化CaMKII（活性CaMKII）的量，而这种增加被CaMKII抑制或PKC抑制所消除。此外，我们通过使用免疫荧光显微镜和免疫电子显微镜研究了活性CaMKII的亚细胞定位的变化。在α_1ARS之前，活性CaMKII仅位于质膜下方。然而，在α_1ARS后，活跃的CaMKII被定位在横向小管附近，大多数L型Ca〜（2+）通道位于该处。根据这些结果，我们提出存在于横小管附近的CaMKII被α_1ARS激活和磷酸化，并且CaMKII激活直接增强了大鼠心室肌细胞中的I_（Ca，L）。

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