M2 and M3 muscarinic receptor-mediated contractions in longitudinal smooth muscle of the ileum studied with receptor knockout mice
| Autor: | Hayato Matsuyama, Yusuke Izumi, Masahisa Yamada, Seiichi Komori, H. Okamoto, Toshihiro Unno, Mai Uchiyama, Takashi Sakamoto, Jürgen Wess |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Pharmacology
medicine.medical_specialty Carbachol Muscarinic acetylcholine receptor M3 Depolarization Stimulation Muscarinic acetylcholine receptor M2 Biology chemistry.chemical_compound Endocrinology chemistry Internal medicine Muscarinic acetylcholine receptor medicine Methoctramine Receptor medicine.drug |
| Zdroj: | British Journal of Pharmacology. 146:98-108 |
| ISSN: | 0007-1188 |
| DOI: | 10.1038/sj.bjp.0706300 |
| Popis: | Isometric contractile responses to carbachol were studied in ileal longitudinal smooth muscle strips from wild-type mice and mice genetically lacking M(2) or M(3) muscarinic receptors, in order to characterize the mechanisms involved in M(2) and M(3) receptor-mediated contractile responses. Single applications of carbachol (0.1-100 microM) produced concentration-dependent contractions in preparations from M(2)-knockout (KO) and M(3)-KO mice, mediated via M(3) and M(2) receptors, respectively, as judged by the sensitivity of contractile responses to blockade by the M(2)-preferring antagonist methoctramine (300 nM) or the M(3)-preferring antagonist 4-DAMP (30 nM). The M(2)-mediated contractions were mimicked in shape by submaximal stimulation with high K(+) concentrations (up to 35 mM), almost abolished by voltage-dependent Ca(2+) channel (VDCC) antagonists or depolarization with 140 mM K(+) medium, and greatly reduced by pertussis toxin (PTX) treatment. The M(3)-mediated contractions were only partially inhibited by VDCC antagonists or 140 mM K(+)-depolarization medium, and remained unaffected by PTX treatment. The contractions observed during high K(+) depolarization consisted of different components, either sensitive or insensitive to extracellular Ca(2+). The carbachol contractions observed with wild-type preparations consisted of PTX-sensitive and -insensitive components. The PTX-sensitive component was functionally significant only at low carbachol concentrations. The results suggest that the M(2) receptor, through PTX-sensitive mechanisms, induces ileal contractions that depend on voltage-dependent Ca(2+) entry, especially associated with action potential discharge, and that the M(3) receptor, through PTX-insensitive mechanisms, induces contractions that depend on voltage-dependent and -independent Ca(2+) entry and intracellular Ca(2+) release. In intact tissues coexpressing M(2) and M(3) receptors, M(2) receptor activity appears functionally relevant only when fractional receptor occupation is relatively small. |
| Databáze: | OpenAIRE |
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