Heme oxygenase-2 is activated by calcium-calmodulin
Heme oxygenase-2 is activated by calcium-calmodulin
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DOI：
10.1074/jbc.c400222200
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发表时间：
2004-07-23
影响因子：
4.8
通讯作者：
Snyder, SH
中科院分区：
文献类型：
--
作者：
Boehning, D;Sedaghat, L;Snyder, SH
血红素加氧酶家族催化血红素代谢为胆绿素、亚铁和一氧化碳 (CO)。至少存在两种亚型：血红素加氧酶-1 (HO1) 和血红素加氧酶-2 (HO2)，它们由不同的基因编码。 HO2 在神经元中选择性富集，大量证据表明 HO2 衍生的 CO 作为神经递质/神经调节剂发挥作用。然而，神经元活动过程中 HO2 快速激活的分子机制尚未被描述。通过酵母双杂交筛选，我们确定钙调蛋白是 HO2 活性的潜在调节剂。钙调蛋白通过典型的 1 - 10 基序以钙依赖性方式与 HO2 具有纳摩尔亲和力结合，导致催化活性增加 3 倍。该基序内的突变会阻断体外和完整细胞中钙调蛋白的结合和酶活性的钙依赖性刺激。钙动员剂离子霉素和谷氨酸刺激原代皮质培养物中的内源性 HO2 活性，建立体内相关性。钙-钙调蛋白提供了一种在神经元活动期间快速瞬时激活 HO2 的机制。
The heme oxygenase family of enzymes catalyzes the metabolism of heme to biliverdin, ferrous iron, and carbon monoxide (CO). At least two isoforms exist, heme oxygenase-1 (HO1) and heme oxygenase-2 (HO2), which are encoded by separate genes. HO2 is selectively enriched in neurons, and substantial evidence suggests that HO2-derived CO functions as a neurotransmitter/ neuromodulator. However, a molecular mechanism for the rapid activation of HO2 during neuronal activity has not been described. Through a yeast two-hybrid screen we identified calmodulin as a potential regulator of HO2 activity. Calmodulin binds with nanomolar affinity to HO2 in a calcium-dependent manner via a canonical 1 - 10 motif, resulting in a 3-fold increase in catalytic activity. Mutations within this motif block calmodulin binding and calcium-dependent stimulation of enzyme activity in vitro and in intact cells. The calcium mobilizing agents ionomycin and glutamate stimulate endogenous HO2 activity in primary cortical cultures, establishing in vivo relevance. Calcium-calmodulin provides a mechanism for rapid and transient activation of HO2 during neuronal activity.