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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Pharmacological assessment of m1 muscarinic acetylcholine receptor-gq/11 protein coupling in membranes prepared from postmortem human brain tissue.
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Pharmacological assessment of m1 muscarinic acetylcholine receptor-gq/11 protein coupling in membranes prepared from postmortem human brain tissue.

机译：从死后人脑组织制备的膜中m1毒蕈碱型乙酰胆碱受体-gq / 11蛋白偶联的药理学评估。

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摘要

Using a selective Galpha(q/11) protein antibody capture guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding approach, it has been possible to perform a quantitative pharmacological examination of the functional activity of the M(1) muscarinic acetylcholine receptor (mAChR) in membranes prepared from human postmortem cerebral cortex. Oxotremorine-M caused a > or = 2-fold increase in [35S]GTPgammaS-Galpha(q/11) binding with a pEC(50) of 6.06 +/- 0.16 in Brodmann's areas 23 and 25 that was almost completely inhibited by preincubation of membranes with the M(1) mAChR subtype-selective antagonist muscarinic toxin-7. In addition, the orthosteric and allosteric agonists, xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] and AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride), increased [35S]-GTPgammaS-Galpha(q/11) binding, but with reduced intrinsic activities, inducing maximal responses that were 42 +/- 1 and 44 +/- 2% of the oxotremorine-M-induced response, respectively. These data indicate that the M(1) receptor is the predominant mAChR subtype coupling to the Galpha(q/11) G protein in these brain regions and that it is possible to quantify the potency and intrinsic activity of full and partial M(1) mAChR receptor agonists in postmortem human brain using a selective Galpha(q/11) protein antibody capture [35S]GTPgammaS binding assay.
机译：使用选择性Galpha（q / 11）蛋白抗体捕获鸟嘌呤5'-O-（3- [35S]硫代）三磷酸（[35S] GTPgammaS）结合方法，可以对功能活性进行定量药理学检查M（1）毒蕈碱型乙酰胆碱受体（mAChR）在人死后大脑皮层制备的膜中的分布Oxotremorine-M导致[35S] GTPgammaS-Galpha（q / 11）结合增加>或= 2倍，在Brodmann区域23和25中的pEC（50）为6.06 +/- 0.16，几乎被预孵育完全抑制了M（1）mAChR亚型选择性拮抗剂毒蕈碱毒素7的膜分离。此外，正构和变构激动剂，xanomeline [3（3-hexyloxy-1,2,5-thiadiazol-4-yl）-1,2,5,6-tetrahydro-1-methylpyridine]和AC-42（4 -正丁基-1- [4-（2-甲基苯基）-4-氧代-1-丁基]-哌啶氯化氢），增加[35S] -GTPgammaS-Galpha（q / 11）的结合，但内在活性降低，诱导的最大反应分别是氧代苯丙氨酸-M诱导的反应的42 +/- 1和44 +/- 2％。这些数据表明，M（1）受体是这些大脑区域中与Galpha（q / 11）G蛋白偶联的主要mAChR亚型，并且有可能量化全部和部分M（1）的效力和内在活性使用选择性Galpha（q / 11）蛋白抗体捕获[35S] GTPgammaS结合测定的死后人类大脑中的mAChR受体激动剂。

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