Combined loss of M2 and M3 muscarinic acetylcholine receptor (mAChR) function in mutant mice increases serotonin airway responsiveness (AR)

The lack of mAChR-subtype selective antagonists has made it difficult to define mAChR airway biology. Mutant murine models lacking specific mAChR subtypes are an important experimental tool to define the in vivo role of M2 and M3 mAChRs in AR. Since lack of M3 function results in loss of in vivo ACh AR ( FASEB J 18:711,2004), 5-hydroxytryptamine (5-HT) can be used to assess changes in respiratory system resistance (Rrs) to an i.v. dose-response challenge (5-100 μg/kg). We investigated the impact of combined loss of M2 and M3 function on the 5HT AR phenotype in M2 -/- /M3 -/- double mutant mice. AR to 5HT was assessed in 8 wildtype (WT) and 6 mutant mice that received Alum adjuvant exposure. The Rrs response to 5HT was significantly greater in the M2 -/- /M3 -/- than in the WT mice (max increase 301%+28 vs 102%+ 28.4; p -/- /M3 -/- mice (100% inhibition). We conclude that loss of M2/M3 function causes an upregulation of 5HT airway responsiveness, which may reflect a change in 5HT receptor expression. Although the molecular mechanisms responsible for the altered phenotype are unclear, our results are an important consideration for the use of mutant mAChR murine models to explore the mechanisms responsible for the development of allergic airway hyperresponsiveness and remodeling. Supported by the Canadian Institutes of Health Research & Ontario Thoracic Society (JF - MOP81211) and the Intramural Research Program of the NIDDKD (JW).