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Multiple muscarinic pathways mediate the suppression of voltage‐gated Ca 2+ channels in mouse intestinal smooth muscle cells
Author(s) -
Tanahashi Yasuyuki,
Unno Toshihiro,
Matsuyama Hayato,
Ishii Toshiaki,
Yamada Masahisa,
Wess Jürgen,
Komori Seiichi
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00475.x
Subject(s) - carbachol , muscarinic acetylcholine receptor , pertussis toxin , endocrinology , medicine , stimulation , receptor , muscarinic acetylcholine receptor m1 , chemistry , muscarinic acetylcholine receptor m2 , biology , myocyte , microbiology and biotechnology , g protein
Background and purpose: Stimulation of muscarinic receptors in intestinal smooth muscle cells results in suppression of voltage‐gated Ca 2+ 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 M 2 KO cells, carbachol (100 µM) 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 M 3 KO 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 M 2 KO and M 3 KO 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 M 3 KO cells, but not in M 2 KO cells. In contrast, the G q/11 inhibitor YM‐254890 strongly inhibited only the I Ca suppression in M 2 KO 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.