86Rb+ efflux mediated by alpha4beta2*-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization.
86Rb+ efflux mediated by alpha4beta2*-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization.
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DOI：
10.1016/j.bcp.2010.06.040
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发表时间：
2010-10-15
影响因子：
5.8
通讯作者：
Collins, Allan C.
中科院分区：
文献类型：
--
作者：
Marks, Michael J.;Meinerz, Natalie M.;Brown, Robert W. B.;Collins, Allan C.
由α4和β2亚基组装而成的烟碱乙酰胆碱受体（nAChR）是脑中表达最密集的亚型。α4β2*-nAChR激动剂激活的浓度-效应曲线是双相的。这种双相激动剂敏感性归因于亚基化学计量的差异。本文描述的研究评价了低浓度地棘蛙素、尼古丁、野靛碱或甲基卡巴胆碱引起的脑α4β2-nAChR功能的脱敏作用，该功能通过乙酰胆碱刺激小鼠丘脑突触体的86 Rb+流出来测量。每种激动剂引起浓度依赖性脱敏。激动剂的效力不同。然而，每种激动剂对高（EC 50 ~ 3 μM）和低（EC 50 ~ 150 μM）乙酰胆碱敏感性的86 Rb+外排脱敏的IC 50值无显著差异。引起脱敏所需的浓度高于其各自的受体结合的KD值。尽管α4β2*-nAChR介导的86 Rb+从小鼠脑流出的两种组分在激动剂激活的EC 50值上显著不同，但它们对暴露于低浓度激动剂的脱敏同样敏感。还通过连续输注0、0.5或4.0 mg/kg/hr的尼古丁对小鼠进行长期处理，并评价尼古丁诱导的脱敏作用。与以前的结果一致，慢性尼古丁治疗增加了地棘蛙素结合位点的密度。急性暴露于尼古丁也引起浓度依赖性脱敏的高敏感性和低敏感性乙酰胆碱刺激的86 Rb+流出皮质和丘脑突触体。虽然慢性尼古丁治疗减少了丘脑的最大86 Rb+流出，但两个脑区的IC 50值均不受慢性尼古丁治疗的影响。
The nicotinic acetylcholine receptors (nAChR) assembled from α4 and β2 subunits are the most densely expressed subtype in the brain. Concentration-effect curves for agonist activation of α4β2*-nAChR are biphasic. This biphasic agonist sensitivity is ascribed to differences in subunit stoichiometry. The studies described here evaluated desensitization elicited by low concentrations of epibatidine, nicotine, cytisine or methylcarbachol of brain α4β2-nAChR function measured with acetylcholine stimulated 86Rb+ efflux from mouse thalamic synaptosomes. Each agonist elicited concentration-dependent desensitization. The agonists differed in potency. However, IC50 values for each agonist for desensitization of 86Rb+ efflux both with high (EC50≈3 μM) and low (EC50≈ 150 μM) acetylcholine sensitivity were not significantly different. Concentrations required to elicit desensitization were higher that their respective KD values for receptor binding. Even though the two components of α4β2*-nAChR mediated 86Rb+ efflux from mouse brain differ markedly in EC50 values for agonist activation, they are equally sensitive to desensitization by exposure to low agonist concentrations. Mice were also chronically treated with nicotine by continuous infusion of 0, 0.5 or 4.0 mg/kg/hr and desensitization induced by nicotine was evaluated. Consistent with previous results, chronic nicotine treatment increased the density of epibatidine binding sites. Acute exposure to nicotine also elicited concentration-dependent desensitization of both high sensitivity and low sensitivity acetylcholine-stimulated 86Rb+ efflux from cortical and thalamic synaptosomes. Although chronic nicotine treatment reduced maximal 86Rb+ efflux from thalamus, IC50 values in both brain regions were unaffected by chronic nicotine treatment.
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