Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice
Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice
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DOI：
10.1124/mol.66.2.260
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发表时间：
2004-08-01
影响因子：
3.6
通讯作者：
Wess, J
中科院分区：
文献类型：
--
作者：
Gautam, D;Heard, TS;Wess, J
Identification of the specific muscarinic acetylcholine receptor (mAChR) subtypes mediating stimulation of salivary secretion is of considerable clinical interest. Recent pharmacological and molecular genetic studies have yielded somewhat confusing and partially contradictory results regarding the involvement of individual mAChRs in this activity. In the present study, we re-examined the roles of M-1 and M-3 mAChRs in muscarinic agonist-mediated stimulation of salivary secretion by using M-1 and M-3 receptor single-knockout ( KO) mice and newly generated M-1/M-3 receptor double-KO mice. When applied at a low dose (1 mg/kg, s.c.), the muscarinic agonist pilocarpine showed significantly reduced secretory activity in both M-1 and M 3 receptor single-KO mice. However, when applied at higher doses, pilocarpine induced only modestly reduced (5 mg/kg, s.c.) or unchanged (15 mg/kg, s.c.) salivation responses, respectively, in M-1 and M-3 receptor single-KO mice, indicating that the presence of either M-1 or M-3 receptors is sufficient to mediate robust salivary output. Quantitative reverse transcriptase-polymerase chain reaction studies with salivary gland tissue showed that the inactivation of the M-1 or M-3 mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes.引人注目的是，毛果芸香碱的促唾液活性在 M-1/M-3 受体双敲除小鼠中被消除。 However, salivary glands from M-1/M-3 receptor double-KO mice remained responsive to stimulation by the beta-adrenergic receptor agonist, (S)-isoproterenol.总的来说，这些研究支持 M-1 和 M-3 受体的混合物介导唾液流的胆碱能刺激的概念。
Identification of the specific muscarinic acetylcholine receptor (mAChR) subtypes mediating stimulation of salivary secretion is of considerable clinical interest. Recent pharmacological and molecular genetic studies have yielded somewhat confusing and partially contradictory results regarding the involvement of individual mAChRs in this activity. In the present study, we re-examined the roles of M-1 and M-3 mAChRs in muscarinic agonist-mediated stimulation of salivary secretion by using M-1 and M-3 receptor single-knockout ( KO) mice and newly generated M-1/M-3 receptor double-KO mice. When applied at a low dose (1 mg/kg, s.c.), the muscarinic agonist pilocarpine showed significantly reduced secretory activity in both M-1 and M 3 receptor single-KO mice. However, when applied at higher doses, pilocarpine induced only modestly reduced (5 mg/kg, s.c.) or unchanged (15 mg/kg, s.c.) salivation responses, respectively, in M-1 and M-3 receptor single-KO mice, indicating that the presence of either M-1 or M-3 receptors is sufficient to mediate robust salivary output. Quantitative reverse transcriptase-polymerase chain reaction studies with salivary gland tissue showed that the inactivation of the M-1 or M-3 mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes. Strikingly, the sialagogue activity of pilocarpine was abolished in M-1/M-3 receptor double-KO mice. However, salivary glands from M-1/M-3 receptor double-KO mice remained responsive to stimulation by the beta-adrenergic receptor agonist, (S)-isoproterenol. Taken together these studies support the concept that a mixture of M-1 and M-3 receptors mediates cholinergic stimulation of salivary flow.