Shigekawa Munekazu, Katanosaka Yuki, Wakabayashi Shigeo
Department of Human Life Sciences, Senri-Kinran University, Fujishiro-dai 5-25-1, Suita, Osaka 565-0873, Japan.
Ann N Y Acad Sci. 2007 Mar;1099:53-63. doi: 10.1196/annals.1387.059.
Na+/Ca2+ exchanger (NCX) activity is markedly inhibited in hypertrophic neonatal rat cardiomyocytes subjected to chronic phenylephrine treatment. This inhibition is reversed partially and independently by acute inhibition of calcineurin and protein kinase C (PKC) activities. Similar NCX inhibition occurs in CCL39 cells expressing cloned wild-type NCX1, when they are infected with adenoviral vectors carrying activated calcineurin A and then treated acutely with phorbol myristoyl acetate or protein phosphatase-1 inhibitors. The data obtained with these cells suggest that calcineurin activity, PKCalpha-mediated NCX1 phosphorylation, and the central loop of NCX1 (possibly its beta1 repeat) are required for the observed NCX inhibition. We observe partial inhibition of NCX activity independent of NCX1 phosphorylation when CCL39 cells are infected with activated calcineurin A but not further treated with phorbol myristoyl acetate or phosphatase inhibitors. Calcineurin thus appears to downregulate NCX activity via two independent mechanisms, one involving NCX1 phosphorylation and the other not involving NCX1 phosphorylation. These data indicate the existence of a novel regulatory mechanism for NCX1 involving calcineurin and PKC, which may be important in cardiac pathology.
在接受慢性去氧肾上腺素处理的肥厚性新生大鼠心肌细胞中，钠/钙交换体（NCX）的活性受到显著抑制。通过急性抑制钙调神经磷酸酶和蛋白激酶C（PKC）的活性，这种抑制作用可部分且独立地被逆转。当表达克隆野生型NCX1的CCL39细胞感染携带活化钙调神经磷酸酶A的腺病毒载体，然后用佛波醇肉豆蔻酸酯乙酸盐或蛋白磷酸酶-1抑制剂进行急性处理时，也会出现类似的NCX抑制现象。从这些细胞获得的数据表明，钙调神经磷酸酶活性、PKCα介导的NCX1磷酸化以及NCX1的中央环（可能是其β1重复序列）是观察到的NCX抑制所必需的。当CCL39细胞感染活化的钙调神经磷酸酶A但不进一步用佛波醇肉豆蔻酸酯乙酸盐或磷酸酶抑制剂处理时，我们观察到NCX活性的部分抑制与NCX1磷酸化无关。因此，钙调神经磷酸酶似乎通过两种独立机制下调NCX活性，一种涉及NCX1磷酸化，另一种不涉及NCX1磷酸化。这些数据表明存在一种涉及钙调神经磷酸酶和PKC的新型NCX1调节机制，这在心脏病理学中可能很重要。
