Multiple muscarinic pathways mediate the suppression of voltage-gated Ca2+channels in mouse intestinal smooth muscle cells
Multiple muscarinic pathways mediate the suppression of voltage-gated Ca2+channels in mouse intestinal smooth muscle cells
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DOI：
10.1111/j.1476-5381.2009.00475.x
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发表时间：
2009-12-01
影响因子：
7.3
通讯作者：
Komori, Seiichi
中科院分区：
文献类型：
--
作者：
Tanahashi, Yasuyuki;Unno, Toshihiro;Komori, Seiichi
背景与目的：刺激肠平滑肌细胞M受体可抑制电压门控性钙通道电流（I-Ca）。然而，很少有人知道哪些受体亚型（S）介导这种effect.Experimental方法：卡巴胆碱对I-Ca的影响进行了研究，在单肠肌细胞从M-2或M-3毒蕈碱受体敲除（KO）和野生型（WT）mice.Key results：在M2 KO细胞，卡巴胆碱（100 μ M）诱导持续I-Ca抑制中看到的WT细胞。然而，这种抑制显著小于在WT细胞中观察到的抑制。卡巴胆碱也抑制I-Ca在M3 KO细胞，但具有阶段性的时间过程。在M-2/M-3-双KO细胞中，卡巴胆碱对I-Ca无影响。WT细胞中的抑制程度大于M2 KO和M3 KO细胞中的I-Ca供应的总和，表明它不是M-2和M-3受体应答的简单混合。G（i/o）抑制剂百日咳毒素可消除M3 KO细胞中的I-Ca抑制，但不能消除M2 KO细胞中的I-Ca抑制。相比之下，G（q/11）抑制剂YM-254890仅强烈抑制M2 KO细胞中的I-Ca抑制。结论：在肠肌细胞中，M-2受体通过G（i/o）蛋白介导I-Ca抑制，而M-3受体通过G（q/11）蛋白介导I-Ca抑制。此外，需要M-2/G（i/o）和M-3/G（q/11）系统的另一种途径可能在诱导持续的I-Ca抑制中起作用。
Background and purpose:Stimulation of muscarinic receptors in intestinal smooth muscle cells results in suppression of voltage-gated Ca2+ channel currents (I-Ca). However, little is known about which receptor subtype(s) mediate this effect.Experimental approach:The effect of carbachol on I-Ca was studied in single intestinal myocytes from M-2 or M-3 muscarinic receptor knockout (KO) and wild-type (WT) mice.Key results:In M2KO cells, carbachol (100 mu M) induced a sustained I-Ca suppression as seen in WT cells. However, this suppression was significantly smaller than that seen in WT cells. Carbachol also suppressed I-Ca in M3KO cells, but with a phasic time course. In M-2/M-3-double KO cells, carbachol had no effect on I-Ca. The extent of the suppression in WT cells was greater than the sum of the I-Ca suppressions in M2KO and M3KO cells, indicating that it is not a simple mixture of M-2 and M-3 receptor responses. The G(i/o) inhibitor, Pertussis toxin, abolished the I-Ca suppression in M3KO cells, but not in M2KO cells. In contrast, the G(q/11) inhibitor YM-254890 strongly inhibited only the I-Ca suppression in M2KO cells. Suppression of I-Ca in WT cells was markedly reduced by either Pertussis toxin or YM-254890.Conclusion and implications:In intestinal myocytes, M-2 receptors mediate a phasic I-Ca suppression via G(i/o) proteins, while M-3 receptors mediate a sustained I-Ca suppression via G(q/11) proteins. In addition, another pathway that requires both M-2/G(i/o) and M-3/G(q/11) systems may be operative in inducing a sustained I-Ca suppression.