Altered M1 Muscarinic Acetylcholine Receptor (CHRM1)-Gαq/11 Coupling in a Schizophrenia Endophenotype
Altered M1 Muscarinic Acetylcholine Receptor (CHRM1)-Gαq/11 Coupling in a Schizophrenia Endophenotype
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DOI：
10.1038/npp.2009.41
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发表时间：
2009-08-01
影响因子：
7.6
通讯作者：
Watson, Jeannette M.
中科院分区：
文献类型：
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作者：
Salah-Uddin, Hasib;Scarr, Elizabeth;Watson, Jeannette M.
毒蕈碱乙酰胆碱受体（CHRM）群体的改变与精神分裂症的病理有关。在这里，我们评估了精神分裂症患者亚群中M-1亚型（CHRM1）的受体功能是否改变，定义为皮质[H-3]-哌嗪（PZP）结合明显（60-80%）减少，并称为“毒毒碱受体缺陷精神分裂症”（MRDS）。使用[S-35]-GTPgS-G α (q/11)免疫捕获方法，我们评估了MRDS组与显示正常PZP结合的精神分裂症患者亚组以及无已知精神或神经疾病史的对照组相比，死后组织中人类皮层（Brodmann区9 (BA9)）中的CHRM1信号是否发生改变。CHRM激动剂（oxotremorine-M）和chrm1选择性激动剂（AC-42）增加了G α (q/11)-[S-35]- gtpgs结合，在对照组和精神分裂症患者亚组中，AC-42产生的反应与完全激动剂oxotremorine-M最大引起的反应的50%相似。然而，与对照组（6.17 +/- 0.10）和非MRDS组（6.05 +/- 0.07）相比，MRDS组(pEC(50) (M) = 5.69 +/- 0.16) oxotremorin -M刺激G α (q/11)-[S-35]- gtpgs结合的效力显著降低。BA9中存在的G α (q/11)蛋白水平不随诊断而变化。与对照组相比，MRDS组BA9膜上最大氧tremorine- m刺激的G α (q/11)-[35 S]- gtpgs结合显著增加。AC-42也有类似的趋势，尽管没有统计学意义。这些数据证明，在精神分裂症患者和对照组的死后人背外侧前额叶皮层制备的膜中，正构和变构作用的CHRM激动剂都可以刺激受体驱动的功能反应（[S-35]-GTPgS结合G α (q/11)）。此外，在一组PZP结合（MRDS）明显降低的精神分裂症患者亚组中，我们发现虽然激动剂的效力可能会降低，但CHRM1-G α (q/11)偶联的功效会增加，这表明在这种内表型的精神分裂症患者中，受体- g蛋白偶联效率发生了适应性变化。神经精神药理学（2009）34,2156-2166；doi: 10.1038 / npp.2009.41;2009年4月29日在线发布
Alterations in muscarinic acetylcholine receptor (CHRM) populations have been implicated in the pathology of schizophrenia. Here we have assessed whether the receptor function of the M-1 subtype (CHRM1) is altered in a sub-population of patients with schizophrenia, defined by marked (60-80%) reductions in cortical [H-3]-pirenzepine (PZP) binding, and termed 'muscarinic receptor-deficit schizophrenia' (MRDS). Using a [S-35]-GTPgS-G alpha(q/11) immunocapture method we have assessed whether CHRM1 signalling in human cortex (Brodmann area 9 (BA9)) is altered in post mortem tissue from a MRDS group compared with a subgroup of patients with schizophrenia displaying normal PZP binding, and controls with no known history of psychiatric or neurological disorders. The CHRM agonist (oxotremorine-M) and a CHRM1-selective agonist (AC-42) increased G alpha(q/11)-[S-35]-GTPgS binding, with AC-42 producing responses that were similar to 50% of those maximally evoked by the full agonist, oxotremorine-M, in control and subgroups of patients with schizophrenia. However, the potency of oxotremorine-M to stimulate G alpha(q/11)-[S-35]-GTPgS binding was significantly decreased in the MRDS group (pEC(50) (M) = 5.69 +/- 0.16) compared with the control group (6.17 +/- 0.10) and the non-MRDS group (6.05 +/- 0.07). The levels of G alpha(q/11) protein present in BA9 did not vary with diagnosis. Maximal oxotremorine-M-stimulated G alpha(q/11)-[35 S]-GTPgS binding in BA9 membranes was significantly increased in the MRDS group compared with the control group. Similar, though non-statistically significant, trends were observed for AC-42. These data provide evidence that both orthosterically and allosterically acting CHRM agonists can stimulate a receptor-driven functional response ([S-35]-GTPgS binding to G alpha(q/11)) in membranes prepared from post mortem human dorsolateral prefrontal cortex of patients with schizophrenia and controls. Furthermore, in a subgroup of patients with schizophrenia displaying markedly decreased PZP binding (MRDS) we have shown that although agonist potency may decrease, the efficacy of CHRM1-G alpha(q/11) coupling increases, suggesting an adaptative change in receptor-G protein coupling efficiency in this endophenotype of patients with schizophrenia. Neuropsychopharmacology (2009) 34, 2156-2166; doi:10.1038/npp.2009.41; published online 29 April 2009