Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine.
Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine.
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有机磷酸盐处理的猪纹状体中毒蕈碱受体的下调。
DOI：
10.1016/0041-008x(90)90159-r
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发表时间：
1990
影响因子：
3.8
通讯作者：
Farley,JM
中科院分区：
文献类型：
--
作者：
Yang,CM;Dwyer,TM;Mohan,PM;Ho,IK;Farley,JM
向雄性猪（约克夏白猪）亚急性（每日）施用二异丙基氟磷酸盐 (DFP)，14 天后可抑制 97% 的胆碱酯酶，并使纹状体匀浆中的 [3H]苯苯甲酸奎宁环酯 ([3H]QNB) 结合位点减少约 50%。受体的最大密度 (Bmax) 从 2.1 ± 0.3 下降至 1.0 ± 0.2 pmole/mg 蛋白质。 [3H]QNB 结合的解离常数 (Kd) 没有显着变化（对照：52.6 ± 10.7 pm；7 天：57 ± 2.8 pm）。 [3H]QNB 结合的卡巴胆碱置换产生了最适合两个结合位点模型的数据。低亲和力状态和高亲和力状态的解离常数分别为 KiL= 115 ± 62 μm (55 ± 3%) 和 KiH= 1.8 ± 0.7 μm (45 ± 3%)。 DFP 治疗 7 天将高亲和力受体的百分比降低至 22 ± 8.6%，但对低亲和力 Kd 和高亲和力 Kd 均没有影响（100 ± 20 和 2 ± 0.6 μm）。添加 Mg2+ 后，纹状体匀浆中的低亲和力受体和高亲和力受体的比例约为 1:1。在 Gpp(NH)p + Mg2+ 存在的情况下，对照组织匀浆中高亲和力受体与低亲和力受体的比例为 3:1（至 26 ± 5%）。这种处理对来自经过 7 天 DFP 处理的猪 (3:1) 的组织匀浆中的这一比例没有影响，因为它已经是 3:1。 [3H]QNB 结合的哌仑西平置换最好通过双结合位点模型来描述，Ki 值为 38 ± 14 和 201 ± 78 nm，分别代表 74% 和 26% 的结合位点。 DFP 处理 (24 ± 5 nm) 7 天后，高亲和力 Kd 值没有变化。哌仑西平抑制 [3H]QNB 结合的位移曲线似乎几乎没有变化。这表明大约 75% 的受体属于 M1 亚型。因此，亚急性施用DFP不仅导致受体数量减少，而且导致激动剂亲和状态比例的变化，这与鸟嘌呤核苷酸结合蛋白和毒蕈碱受体的相互作用有关。
Subacute (daily) administration of diisopropylfluorophosphate (DFP) to male swine (Yorkshire white) resulted in a 97% inhibition of cholinesterase and a decrease of [3H]quinuclidinyl benzilate ([3H]QNB) binding sites in homogenates of striata by ∼ 50% after 14 days. The maximal density of receptors (Bmax) decreased from 2.1 ± 0.3 to 1.0 ± 0.2 pmole/mg protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding (control: 52.6 ± 10.7 pm; 7-day: 57 ± 2.8 pm). Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL= 115 ± 62 μm (55 ± 3%) and KiH= 1.8 ± 0.7 μm (45 ± 3%), respectively, for the low- and high-affinity states. Seven-Day treatment with DFP reduced the percentage of high-affinity receptors to 22 ± 8.6%, but affected neither the low- nor the high-affinity Kd(100 ± 20 and 2 ± 0.6 μm). With the addition of Mg2+, striatal homogenates had low- and high-affinity receptors in the proportion of approximately 1 to 1. In the presence of Gpp(NH)p + Mg2+the ratio of high- to low-affinity receptors was 3:1 in homogenates of control tissue (to 26 ± 5%). This treatment had no effect on this ratio in homogenates of tissue from 7-day DFP-treated swine (3:1) since it was already 3:1. Pirenzepine displacement of [3H]QNB binding was best described by a two-binding site model, with Kivalues of 38 ± 14 and 201 ± 78 nm, which represent 74 and 26% of the binding sites, respectively. The high affinity Kdvalue was unchanged following 7 days of DFP treatment (24 ± 5 nm). There appears to be little change in the displacement curves for pirenzepine inhibition of [3H]QNB binding. This suggests that about 75% of the receptors are of the M1subtype. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the proportion of agonist affinity states which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor.