A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels
A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels
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DOI：
10.1007/s00213-008-1095-x
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发表时间：
2008-07-01
影响因子：
3.4
通讯作者：
Lang, Undine E.
中科院分区：
文献类型：
--
作者：
Fedorenko, Olga;Strutz-Seebohm, Nathalie;Lang, Undine E.
基本原理磷脂酰肌醇-4-磷酸5-激酶II α（PIP 5 K2 A）和精神分裂症之间的关联的证据最近获得并在几个样本中重复。PIP 5 K2 A通过磷脂酰肌醇-4，5-二磷酸（PIP 2）合成控制KCNQ通道的功能。有趣的是，最近的数据表明，KCNQ通道抑制多巴胺能神经元的基础活动和多巴胺能放电。目的探讨PIP 5 K2 A对精神分裂症患者行为的影响，并探讨PIP 5 K2 A对KCNQ 2、KCNQ 5、KCNQ 2/KCNQ 3、KCNQ 2/KCNQ 4、KCNQ 5/KCNQ 5、KCNQ 5/KCNQ 6、KCNQ 5/KCNQ 6、KCNQ 6/KCNQ 7、KCNQ 7/KCNQ 8、KCNQ 8/KCNQ 8、KCNQ 8/KCNQ 8、KCNQ 9/KCNQ 8、KCNQ 9/KCNQ 8的作用。结果发现野生型PIP 5 K2 A激活神经元M通道相关分子KCNQ 2/KCNQ 3和KCNQ 3/KCNQ 5，而精神分裂症相关突变体（N251 S）-PIP 5 K2 A不激活。同源KCNQ 2和KCNQ 5通道没有被激酶激活，表明KCNQ 3在通道复合物中的存在是激酶介导的作用所必需的。急性应用PI（4，5）P-2和PIP 2清除剂表明突变N251 S使激酶PIP 5 K2 A失活。结论我们的研究结果表明，精神分裂症相关的激酶突变的结果在减少KCNQ通道功能，从而可能解释多巴胺能控制的精神分裂症患者的损失。此外，多巴胺能药物的成瘾潜力，经常观察到精神分裂症患者可能是由这种机制来解释。至少，（N251 S）-PIP 5 K2 A刺激神经元M通道的不足可能有助于精神分裂症的临床表型。
Rationale Evidence for an association between phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) and schizophrenia was recently obtained and replicated in several samples. PIP5K2A controls the function of KCNQ channels via phosphatidylinositol-4,5-bisphosphate(PIP2) synthesis. Interestingly, recent data suggest that KCNQ channels suppress basal activity of dopaminergic neurons and dopaminergic firing. Activation of KCNQ accordingly attenuates the central stimulating effects of dopamine, cocaine, methylphenidate, and phenylcyclidine.Objective The aim of this study was to explore the functional relevance of PIP5K2A, which might influence schizophrenic behavior.Materials and methods Here, we study the effects of the neuronal PIP5K2A on KCNQ2, KCNQ5, KCNQ2/KCNQ3, and KCNQ3/KCNQ5 in the Xenopus expression system.Results We find that wild-type PIP5K2A but not the schizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5, the molecular correlate of neuronal M channels. Homomeric KCNQ2 and KCNQ5 channels were not activated by the kinase indicating that the presence of KCNQ3 in the channel complex is required for the kinase-mediated effects. Acute application of PI(4,5)P-2 and a PIP2 scavenger indicates that the mutation N251S renders the kinase PIP5K2A inactive.Conclusions Our results suggest that the schizophrenia-linked mutation of the kinase results in reduced KCNQ channel function and thereby might explain the loss of dopaminergic control in schizophrenic patients. Moreover, the addictive potential of dopaminergic drugs often observed in schizophrenic patients might be explained by this mechanism. At least, the insufficiency of (N251S)-PIP5K2A to stimulate neuronal M channels may contribute to the clinical phenotype of schizophrenia.