Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1
Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1
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DOI：
10.1074/jbc.m604474200
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发表时间：
2007-01-05
影响因子：
4.8
通讯作者：
Yoshikawa, Takeo
中科院分区：
文献类型：
--
作者：
Ohnishi, Tetsuo;Ohba, Hisako;Yoshikawa, Takeo
锂被用于临床治疗双相情感障碍，这是一种患者在躁狂和抑郁之间情绪波动的疾病。尽管锂的作用方式仍然不清楚，但一个可能的主要靶点被认为是肌醇单磷酸酶(IMPase)的活性。在哺乳动物中已鉴定出两个IMPase基因，分别是肌醇单磷酸酶1(IMPA1)和肌醇单磷酸酶2(IMPA2)。一些遗传证据表明，IMPA2不仅与双相情感障碍有关，而且与精神分裂症和热性癫痫的发病机制有关。然而，人们对这种蛋白质知之甚少，尽管根据它与IMPA1的同源性，人们预测它具有锂抑制的IMPase活性。在这里，我们提出了第一个生化研究，比较了IMPA2和IMPA1的酶活性。我们证明在体内，IMPA2与IMPA1形成同源二聚体，但不形成异源二聚体。重组IMPA2表现出IMPase活性，尽管最大活性需要更高的镁浓度和更高的pH。IMPA2对肌醇一磷酸的活性明显低于IMPA1。因此，我们筛选了可以被IMPA2更有效地去磷酸化的其他底物，但没有找到任何底物。重要的是，当以肌醇一磷酸为底物时，IMPA2的IMPase活性在高锂和限制镁浓度下受到抑制。这一动力学使其有别于IMPA1。我们还观察到IMPA1和IMPA2在包括脑、小肠和肾脏在内的一些组织中差异表达的特征模式。这些数据表明，IMPA2在体内具有与IMPA1不同的功能。
Lithium is used in the clinical treatment of bipolar disorder, a disease where patients suffer mood swings between mania and depression. Although the mode of action of lithium remains elusive, a putative primary target is thought to be inositol monophosphatase (IMPase) activity. Two IMPase genes have been identified in mammals, the well characterized myo-inositol monophosphatase 1 (IMPA1) and myo-inositol monophosphatase 2 (IMPA2). Several lines of genetic evidence have implicated IMPA2 in the pathogenesis of not only bipolar disorder but also schizophrenia and febrile seizures. However, little is known about the protein, although it is predicted to have lithium-inhibitable IMPase activity based on its homology to IMPA1. Here we present the first biochemical study comparing the enzyme activity of IMPA2 to that of IMPA1. We demonstrate that in vivo, IMPA2 forms homodimers but no heterodimers with IMPA1. Recombinant IMPA2 exhibits IMPase activity, although maximal activity requires higher concentrations of magnesium and a higher pH. IMPA2 shows significantly lower activity toward myo-inositol monophosphate than IMPA1. We therefore screened for additional substrates that could be more efficiently dephosphorylated by IMPA2, but failed to find any. Importantly, when using myo-inositol monophosphate as a substrate, the IMPase activity of IMPA2 was inhibited at high lithium and restricted magnesium concentrations. This kinetics distinguishes it from IMPA1. We also observed a characteristic pattern of differential expression between IMPA1 and IMPA2 in a selection of tissues including the brain, small intestine, and kidney. These data suggest that IMPA2 has a separate function in vivo from that of IMPA1.