PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder
PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder
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DOI：
10.1038/sj.tpj.6500400
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发表时间：
2007-04-01
影响因子：
2.8
通讯作者：
Chumakov, I.
中科院分区：
文献类型：
--
作者：
Borsotto, M.;Cavarec, L.;Chumakov, I.
许多双相情感障碍（BD）的易感基因已被确定，但负责疾病的分子机制仍有待阐明。在基因座4p 16中，鉴定了几个候选基因，但没有一个明确显示与BD相关。在该区域中，PPP 2 R2 C基因编码蛋白磷酸酶2A（PP 2 A-B gamma）的B gamma调节亚基。首先，我们确定，在两个不同的人群中，单核苷酸多态性和风险单倍型，该基因与BD。然后，以B γ亚基为诱饵，利用酵母双杂交技术筛选人脑cDNA文库。这使我们发现了KCNQ 2通道的两个新的剪接变体和KCNQ 2通道本身。这种不寻常的K+通道具有特别有趣的功能特性，属于已知与其他几种单基因疾病有关的通道家族。在其中一个BD人群中，我们还发现了KCNQ 2基因与BD之间的遗传关联。我们发现，KCNQ 2剪接变体与天然通道不同，其缩短的C-末端序列是独特的，因为它们是活跃的，并对KCNQ 2野生型（wt）通道活性产生显性负效应。我们还表明，PP 2A-B γ亚基显着增加由KCNQ 2 wt产生的电流，KCNQ 2 wt是一种通常被磷酸化抑制的通道。激酶糖原合成酶激酶3 β（GSK 3 β）被认为是锂的一个有趣的靶点，锂是BD中使用的经典药物。GSK 3 β磷酸化KCNQ 2通道，这种磷酸化被Li+降低。
Many bipolar affective disorder ( BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the B gamma-regulatory subunit of the protein phosphatase 2A (PP2A-B gamma). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the B gamma subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K+ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-B gamma subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3 beta) is considered as an interesting target of lithium, the classical drug used in BD. GSK3 beta phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li+.