Identification of a serotonin/glutamate receptor complex implicated in psychosis
Identification of a serotonin/glutamate receptor complex implicated in psychosis
复制标题
DOI：
10.1038/nature06612
复制
发表时间：
2008-03-06
期刊：
影响因子：
64.8
通讯作者：
Sealfon, Stuart C.
中科院分区：
文献类型：
--
作者：
Gonzalez-Maeso, Javier;Ang, Rosalind L.;Sealfon, Stuart C.
与精神分裂症相关的精神病的特点是感觉处理和知觉的改变(1,2)。一些抗精神病药物因其对血清素 5-HT2A 受体 (2AR) 的高亲和力而被鉴定(3,4)。与代谢型谷氨酸受体 (mGluR) 相互作用的药物也具有治疗精神分裂症的潜力(5-7)。致幻药物（例如裸盖菇素和麦角酰二乙胺）的作用需要 2AR(8-10)，并且类似于精神分裂症的一些核心症状(10-12)。在这里，我们证明 mGluR2 通过特定的跨膜螺旋结构域与 2AR（不相关的 G 蛋白偶联受体家族的成员）相互作用，在大脑皮层中形成功能复合物。当致幻药物靶向时，2AR - mGluR2 复合物会触发独特的细胞反应，并且 mGluR2 的激活会消除致幻剂特异性信号传导和行为反应。在未经治疗的精神分裂症受试者的死后大脑中，2AR 上调，mGluR2 下调，这种模式可能导致精神病。这些调节变化表明2AR mGluR2复合物可能参与精神分裂症皮质过程的改变，因此该复合物是治疗精神病的一个有前途的新靶点。
The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception(1,2). Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR)(3,4). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia(5-7). The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR(8-10) and resemble some of the core symptoms of schizophrenia(10-12). Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G- protein- coupled receptor family, to form functional complexes in brain cortex. The 2AR - mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen- specific signalling and behavioural responses. In post- mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.