Usiello A, Baik J H, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, Piazza P V, Borrelli E
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP, Illkirch, C.U. de Strasbourg, France.
Nature. 2000 Nov 9;408(6809):199-203. doi: 10.1038/35041572.
Signalling through dopamine D2 receptors governs physiological functions related to locomotion, hormone production and drug abuse. D2 receptors are also known targets of antipsychotic drugs that are used to treat neuropsychiatric disorders such as schizophrenia. By a mechanism of alternative splicing, the D2 receptor gene encodes two molecularly distinct isoforms, D2S and D2L, previously thought to have the same function. Here we show that these receptors have distinct functions in vivo; D2L acts mainly at postsynaptic sites and D2S serves presynaptic autoreceptor functions. The cataleptic effects of the widely used antipsychotic haloperidol are absent in D2L-deficient mice. This suggests that D2L is targeted by haloperidol, with implications for treatment of neuropsychiatric disorders. The absence of D2L reveals that D2S inhibits D1 receptor-mediated functions, uncovering a circuit of signalling interference between dopamine receptors.
通过多巴胺D2受体发出的信号控制着与运动、激素产生和药物滥用相关的生理功能。D2受体也是用于治疗精神疾病如精神分裂症的抗精神病药物的已知靶点。通过可变剪接机制，D2受体基因编码两种分子上不同的亚型，D2S和D2L，以前认为它们具有相同的功能。在这里，我们表明这些受体在体内具有不同的功能；D2L主要作用于突触后位点，而D2S发挥突触前自身受体功能。在缺乏D2L的小鼠中，广泛使用的抗精神病药物氟哌啶醇的僵住效应不存在。这表明氟哌啶醇作用于D2L，这对神经精神疾病的治疗具有启示意义。D2L的缺失表明D2S抑制D1受体介导的功能，揭示了多巴胺受体之间的信号干扰回路。
