Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1 and M3 muscarinic receptors.
Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1 and M3 muscarinic receptors.
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DOI：
10.1152/ajpgi.00105.2004
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发表时间：
2005-09
期刊：
影响因子：
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通讯作者：
G. Xie;C. Drachenberg;M. Yamada;J. Wess;J. Raufman
中科院分区：
文献类型：
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作者：
G. Xie;C. Drachenberg;M. Yamada;J. Wess;J. Raufman
毒蕈碱胆碱能机制在刺激胃蛋白酶原分泌中起关键作用。使用拮抗剂的研究表明，M3受体亚型（M3 R）在介导胃蛋白酶原分泌中起着突出的作用，但原位杂交表明M1受体（M1 R）在大鼠主细胞中的表达。我们使用缺乏M1（M1 R-/-）或M3（M3 R-/-）受体或缺乏这两种受体（M（1/3）R-/-）的小鼠来确定M1 R和M3 R在介导胆碱能激动剂诱导的胃蛋白酶原分泌中的作用。本文采用家兔和大鼠胃的胃蛋白酶原测定方法，测定了小鼠胃腺分泌胃蛋白酶原的能力。在野生型（WT）小鼠中，卡巴胆碱和CCK的最大浓度分别导致胃蛋白酶原分泌增加3.0倍和2.5倍。卡巴胆碱诱导的M1 R-/-小鼠胃腺最大分泌量降低25%。相比之下，当比较M3 R-/-与WT腺体时，卡巴胆碱效力仅轻微降低，并且功效无变化。为了探讨M1 R和M3 R参与卡巴胆碱介导的胃蛋白酶原分泌的可能性，我们检查了M（1/3）R-/-双敲除小鼠腺体的分泌物。引人注目的是，卡巴胆碱诱导的胃蛋白酶原分泌几乎被废除的腺体从M（1/3）R-/-小鼠，而CCK诱导的分泌没有改变。原位杂交小鼠M1 R和M3 R mRNA在胃粘膜从WT小鼠揭示了丰富的信号在主细胞的细胞质中的受体亚型。这些数据清楚地表明，在胃主细胞中，M1和M3受体的混合物介导胃蛋白酶原分泌的胆碱能刺激，并且没有其他毒蕈碱受体亚型参与这种活动。小鼠分泌模型的建立有助于转基因小鼠研究胃蛋白酶原分泌的调节。
Muscarinic cholinergic mechanisms play a key role in stimulating gastric pepsinogen secretion. Studies using antagonists suggested that the M3 receptor subtype (M3R) plays a prominent role in mediating pepsinogen secretion, but in situ hybridization indicated expression of M1 receptor (M1R) in rat chief cells. We used mice that were deficient in either the M1 (M1R-/-) or M3 (M3R-/-) receptor or that lacked both receptors (M(1/3)R-/-) to determine the role of M1R and M3R in mediating cholinergic agonist-induced pepsinogen secretion. Pepsinogen secretion from murine gastric glands was determined by adapting methods used for rabbit and rat stomach. In wild-type (WT) mice, maximal concentrations of carbachol and CCK caused a 3.0- and 2.5-fold increase in pepsinogen secretion, respectively. Maximal carbachol-induced secretion from M1R-/- mouse gastric glands was decreased by 25%. In contrast, there was only a slight decrease in carbachol potency and no change in efficacy when comparing M3R-/- with WT glands. To explore the possibility that both M1R and M3R are involved in carbachol-mediated pepsinogen secretion, we examined secretion from glands prepared from M(1/3)R-/- double-knockout mice. Strikingly, carbachol-induced pepsinogen secretion was nearly abolished in glands from M(1/3)R-/- mice, whereas CCK-induced secretion was not altered. In situ hybridization for murine M1R and M3R mRNA in gastric mucosa from WT mice revealed abundant signals for both receptor subtypes in the cytoplasm of chief cells. These data clearly indicate that, in gastric chief cells, a mixture of M1 and M3 receptors mediates cholinergic stimulation of pepsinogen secretion and that no other muscarinic receptor subtypes are involved in this activity. The development of a murine secretory model facilitates use of transgenic mice to investigate the regulation of pepsinogen secretion.