Muscarinic agonist-mediated heterologous desensitization in isolated ileum requires activation of both muscarinic M2 and M3 receptors
Muscarinic agonist-mediated heterologous desensitization in isolated ileum requires activation of both muscarinic M2 and M3 receptors
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DOI：
10.1124/jpet.103.055327
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发表时间：
2004-01-01
影响因子：
3.5
通讯作者：
Ehlert, FJ
中科院分区：
文献类型：
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作者：
Griffin, MT;Matsui, M;Ehlert, FJ
我们研究了介导离体回肠短期异源脱敏的毒蕈碱受体亚型。用乙酰胆碱（30 μ M）处理C57 BL/6小鼠的回肠20分钟，随后引起对前列腺素F-2 α（PGF（2 α））和毒蕈碱激动剂oxotremorine-M的收缩敏感性降低。这种亚敏感性的特征是激动剂的EC 50值分别增加7倍和3倍，对最大反应无显著影响。在M-2和M-3毒蕈碱受体敲除小鼠中，对PGF（2 α）的亚敏感性得到了预防。类似地，在M-2敲除小鼠中防止了对氧震颤素-M的亚敏感性。乙酰胆碱介导的脱敏组胺诱导的收缩在豚鼠回肠抑制M-2-和M-3-选择性毒蕈碱拮抗剂具有高效力，虽然仔细分析的数据表明行为更符合M-2拮抗配置文件。建模研究表明，两种受体亚型激活后的竞争性拮抗反应应表现出与最不敏感的信号通路相似的药理学特征。我们的研究结果表明，毒蕈碱激动剂介导的短期异源脱敏的肠平滑肌是偶然的M-2和M-3毒蕈碱受体的激活和激活的受体本身是不足以引起脱敏。
We investigated the subtypes of the muscarinic receptor mediating short-term heterologous desensitization in the isolated ileum. Treatment of the ileum from C57BL/6 mice with acetylcholine (30 muM) for 20 min caused a subsequent decrease in contractile sensitivity to both prostaglandin F-2alpha (PGF(2alpha)) and the muscarinic agonist, oxotremorine-M. This subsensitivity was characterized by 7- and 3-fold increases in the EC50 values of the agonists, respectively, with no significant effect on the maximal response. The subsensitivity to PGF(2alpha) was prevented in both M-2 and M-3 muscarinic receptor knockout mice. Similarly, the subsensitivity to oxotremorine-M was prevented in M-2 knockout mice. Acetylcholine-mediated desensitization of histamine-induced contractions in the guinea pig ileum was inhibited by both M-2- and M-3-selective muscarinic antagonists with high potency, although careful analysis of the data suggested behavior more consistent with an M-2 antagonistic profile. Modeling studies showed that the competitive antagonism of response contingent upon activation of two receptor subtypes should exhibit a pharmacological profile similar to that of the least sensitive signaling pathway. Our results demonstrate that muscarinic agonist-mediated short-term heterologous desensitization of intestinal smooth muscle is contingent upon activation of both M-2 and M-3 muscarinic receptors and that activation of either receptor by itself is insufficient to cause desensitization.