M3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice
M3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice
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DOI：
10.1113/jphysiol.2004.064626
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发表时间：
2004-07-15
影响因子：
5.5
通讯作者：
Mikoshiba, K
中科院分区：
文献类型：
--
作者：
Nakamura, T;Matsui, M;Mikoshiba, K
M-1和M-3亚型是唾液腺中主要的毒蕈碱型乙酰胆碱受体，据报道M-3更丰富。然而，尽管最初报道了M-3基因敲除（M3 KO）小鼠的流涎异常，但仍不清楚哪种亚型在生理流涎中具有功能相关性。在本研究中，使用缺乏特定毒蕈碱受体亚型的小鼠检查了唾液分泌功能。卡巴胆碱诱导的[Ca 2 +]（i）增加在M3 KO小鼠的下颌下腺细胞中明显受损，而在M-1/M3 KO小鼠的下颌下腺细胞中完全不存在。这表明M-3和M-1在胆碱能诱导的[Ca 2 +]（i）增加中分别起主要和次要作用。二维钙离子成像分析显示，斑片状分布的M-1在颌下腺腺泡，在无处不在的分布M-3。在体内给予高剂量的毛果芸香碱（10 mg/kg，s.c.）M3 KO小鼠的唾液分泌与野生型小鼠相当，而M-1/M3 KO小鼠中未诱导唾液分泌，表明M3 KO小鼠中的唾液分泌是由M-1介导的[Ca 2 +]（i）增加引起的。相比之下，较低剂量的毛果芸香碱（1 mg/kg，s.c.）未能在M3 KO小鼠中诱导流涎，但在野生型小鼠中诱导大量流涎，表明M-3介导的流涎具有比M-1介导的流涎更低的阈值。此外，M3 KO小鼠（而不是M1 KO小鼠）进食干粮困难，表现为进食期间频繁饮酒，这表明进食期间的唾液分泌是由M-3介导的，而M-1在其中不起实际作用。这些结果表明M-3亚型对于唾液分泌的副交感神经控制至关重要，也是口干症药物治疗和基因治疗的合理靶点。包括干燥综合征
The M-1 and M-3 subtypes are the major muscarinic acetylcholine receptors in the salivary gland and M-3 is reported to be more abundant. However, despite initial reports of salivation abnormalities in M-3-knockout (M3KO) mice, it is still unclear which subtype is functionally relevant in physiological salivation. In the present study, salivary secretory function was examined using mice lacking specific subtype(s) of muscarinic receptor. The carbachol-induced [Ca2+](i) increase was markedly impaired in submandibular gland cells from M3KO mice and completely absent in those from M-1/M3KO mice. This demonstrates that M-3 and M-1 play major and minor roles, respectively, in the cholinergically induced [Ca2+](i) increase. Two-dimensional Ca2+-imaging analysis revealed the patchy distribution of M-1 in submandibular gland acini, in contrast to the ubiquitous distribution Of M-3. In vivo administration of a high dose of pilocarpine (10 mg kg(-1), s.c.) to M3KO mice caused salivation comparable to that in wild-type mice, while no salivation was induced in M-1/M3KO mice, indicating that salivation in M3KO mice is caused by an M-1-mediated [Ca2+](i) increase. In contrast, a lower dose of pilocarpine (1 mg kg(-1), s.c.) failed to induce salivation in M3KO mice, but induced abundant salivation in wild-type mice, indicating that M-3-mediated salivation has a lower threshold than M-1-mediated salivation. In addition, M3KO mice, but not M1KO mice, had difficulty in eating dry food, as shown by frequent drinking during feeding, suggesting that salivation during eating is mediated by M-3 and that M-1 plays no practical role in it. These results show that the M-3 subtype is essential for parasympathetic control of salivation and a reasonable target for the drug treatment and gene therapy of xerostomia, including Sjogren's syndrome.