Serotonin 5-HT2A receptors (5-HT2ARs) have been implicated in schizophrenia. However, postmortem studies on 5-HT2ARs expression and functionality in schizophrenia are scarce. The 5-HT2AR mRNA and immunoreactive protein expression were evaluated in postmortem tissue from dorsolateral prefrontal cortex (DLPFC) of antipsychotic-free (n = 18) and antipsychotic-treated (n = 9) subjects with schizophrenia, and matched controls (n = 27). Functional coupling of 5-HT2AR to G-proteins was tested by measuring the activation induced by the agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride ((±)DOI) in antibody-capture [35S]GTPγS scintillation proximity assays (SPA). In antipsychotic-free schizophrenia subjects, 5-HT2AR mRNA expression and protein immunoreactivity in total homogenates was similar to controls. In contrast, in antipsychotic-treated schizophrenia subjects, lower mRNA expression (60±9% vs controls) and a trend to reduced protein immunoreactivity (86±5% vs antipsychotic-free subjects) just in membrane-enriched fractions was observed. [35S]GTPγS SPA revealed a significant ~6% higher stimulation of Gαi1-protein by (±)DOI in schizophrenia, whereas activation of the canonical Gαq/11-protein pathway by (±)DOI remained unchanged. Expression of Gαi1- and Gαq/11-proteins did not differ between groups. Accordingly, in rats chronically treated with clozapine, but not with haloperidol, a 30-40% reduction was observed in 5-HT2AR mRNA expression, 5-HT2AR protein immunoreactivity and [3H]ketanserin binding in brain cortical membranes. Overall, the data suggest a supersensitive 5-HT2AR signaling through inhibitory Gαi1-proteins in schizophrenia. Together with previous results, a dysfunctional pro-hallucinogenic agonist-sensitive 5-HT2AR conformation in postmortem DLPFC of subjects with schizophrenia is proposed. Atypical antipsychotic treatment would contribute to counterbalance this 5-HT2AR supersensitivity by reducing receptor expression.

中文翻译：

---

精神分裂症患者死后额叶皮层中血清素 5-HT2A 受体的表达和功能：通过 Gαi1 蛋白的选择性偏向激动

血清素 5-HT2A 受体 (5-HT2ARs) 与精神分裂症有关。然而，关于精神分裂症中 5-HT2ARs 表达和功能的死后研究很少。在来自无抗精神病药（n = 18）和抗精神病药治疗（n = 9）精神分裂症受试者的背外侧前额叶皮层（DLPFC）的死后组织中评估 5-HT2AR mRNA 和免疫反应蛋白表达，以及匹配的对照（n = 27） ）。通过测量激动剂 (±)-2,5-二甲氧基-4-碘苯丙胺盐酸盐 ((±)DOI) 在抗体捕获 [35S]GTPγS 闪烁接近中诱导的活化来测试 5-HT2AR 与 G 蛋白的功能偶联化验（SPA）。在不含抗精神病药的精神分裂症受试者中，总匀浆中的 5-HT2AR mRNA 表达和蛋白质免疫反应性与对照组相似。相比之下，在接受抗精神病药治疗的精神分裂症受试者中，仅在富含膜的部分中观察到较低的 mRNA 表达（60±9% 与对照组相比）和蛋白质免疫反应性降低的趋势（86±5% 与不含抗精神病药的受试者）。[35S]GTPγS SPA 显示，在精神分裂症中，(±)DOI 对 Gαi1 蛋白的刺激显着增加了约 6%，而 (±)DOI 对经典 Gαq/11 蛋白通路的激活保持不变。Gαi1- 和 Gαq/11- 蛋白的表达在组间没有差异。因此，在用氯氮平而非氟哌啶醇长期治疗的大鼠中，观察到 5-HT2AR mRNA 表达、5-HT2AR 蛋白免疫反应性和 [3H] 酮色林在脑皮质膜中的结合降低了 30-40%。总体而言，数据表明精神分裂症中通过抑制性 Gαi1 蛋白的超敏感 5-HT2AR 信号传导。与先前的结果一起，提出了精神分裂症患者死后 DLPFC 中功能失调的促致幻激动剂敏感 5-HT2AR 构象。非典型抗精神病药物治疗将有助于通过减少受体表达来抵消这种 5-HT2AR 超敏反应。