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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Serotonin transporter phosphorylation by cGMP-dependent protein kinase is altered by a mutation associated with obsessive compulsive disorder.
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Serotonin transporter phosphorylation by cGMP-dependent protein kinase is altered by a mutation associated with obsessive compulsive disorder.

机译：与强迫症有关的突变改变了cGMP依赖性蛋白激酶引起的血清素转运蛋白磷酸化。

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摘要

Human serotonin transporter (hSERT) activity expressed in HeLa cells was stimulated by agents that release nitric oxide, stimulate soluble guanylyl cyclase, or activate cGMP-dependent protein kinase (PKG). This stimulation was blocked by a PKG inhibitor. A naturally occurring mutation, I425V, associated with obsessive-compulsive disorder and other neuropsychiatric disorders, activated hSERT and eliminated stimulation via the PKG pathway. Inhibitors of soluble guanylyl cyclase or PKG decreased activity of the I425V mutant, but not wild type, indicating that both wild-type and mutant transporters could exist in both high and low activity forms. Mutation of Thr-276 in the fifth transmembrane domain (TM5) to alanine or aspartate prevented activation of wild-type hSERT through the PKG pathway and also blocked the inhibition of I425V activity by inhibitors of the pathway. The accessibility of positions in TM5 near Thr-276 was modified in T276D, but not in I425V. These results are consistent with the hypothesis that PKG phosphorylates hSERT at Thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by TM5. The effect of the I425V mutation may shift the balance of hSERT toward the phosphorylated form, possibly by interfering with the action of a phosphatase. However, association of hSERT with protein phosphatase 2A was not decreased in the I425V mutant.
机译：通过释放一氧化氮，刺激可溶性鸟苷酸环化酶或激活cGMP依赖性蛋白激酶（PKG）的药物刺激HeLa细胞中表达的人类血清素转运蛋白（hSERT）活性。这种刺激被PKG抑制剂阻断。与强迫症和其他神经精神疾病有关的天然突变I425V激活hSERT并通过PKG途径消除刺激。可溶性鸟苷酰环化酶或PKG的抑制剂会降低I425V突变体的活性，但不会降低野生型的活性，这表明野生型和突变体转运蛋白都可以高活性和低活性形式存在。第五个跨膜结构域（TM5）中的Thr-276突变为丙氨酸或天冬氨酸，可阻止野生型hSERT通过PKG途径活化，也可阻止该途径的抑制剂抑制I425V活性。 T276D中修改了Thr5 276附近TM5中位置的可访问性，但I425V中未修改。这些结果与PKG在Thr-276处磷酸化hSERT并通过修饰部分由TM5形成的底物渗透途径增加其活性的假设相符。 I425V突变的作用可能会干扰磷酸酶的作用，从而使hSERT的平衡向磷酸化形式转移。但是，在I425V突变体中，hSERT与蛋白磷酸酶2A的结合并没有减少。

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