Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Cell. 2011 Nov 23;147(5):1011-23. doi: 10.1016/j.cell.2011.09.055.
Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT(2A) G protein-coupled receptor (GPCR), the 2AR, which signals via a G(q) heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the G(i)-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi- and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.
非典型抗精神病药物，如氯氮平和利培酮，对血清素 5-HT(2A)G 蛋白偶联受体 (GPCR)、2AR 具有很高的亲和力，2AR 通过 G(q)异三聚体 G 蛋白传递信号。密切相关的非抗精神病药物，如利坦色林和麦角乙脲，也能阻断 2AR 功能，但它们没有类似的神经心理学作用。为什么有些但不是所有的 2AR 抑制剂都表现出抗精神病特性仍未解决。我们现在表明，2AR 和 G(i) 连接的 GPCR，代谢型谷氨酸 2 受体 (mGluR2) 之间的异源二聚体复合物整合配体输入，调节信号输出和行为变化。血清素能和谷氨酸能药物结合 mGluR2/2AR 异源复合物，然后平衡 Gi 和 Gq 依赖性信号。我们发现 mGluR2/2AR 介导的 Gi 和 Gq 活性变化可以预测各种药物化合物的精神活性行为效应。这些观察结果为抗精神病作用提供了机制上的见解，可能为包括精神分裂症和痴呆在内的各种疾病的治疗策略提供进展。
