Abstract
The mechanisms of controlling airway smooth muscle (ASM) tone are of utmost clinical importance as inappropriate constriction is a hallmark in asthma and chronic obstructive pulmonary disease. Receptors for acetylcholine and serotonin, two relevant mediators in this context, appear to be incorporated in specialized, cholesterol-rich domains of the plasma membrane, termed caveolae due to their invaginated shape. The structural protein caveolin-1 partly accounts for anchoring of these receptors. We here determined the role of the other major caveolar protein, caveolin-3 (cav-3), in orchestrating cholinergic and serotonergic ASM responses, utilizing newly generated cav-3 deficient mice. Cav-3 deficiency fully abrogated serotonin-induced constriction of extrapulmonary airways in organ baths while leaving intrapulmonary airways unaffected, as assessed in precision cut lung slices. The selective expression of cav-3 in tracheal, but not intrapulmonary bronchial epithelial cells, revealed by immunohistochemistry, might explain the differential effects of cav-3 deficiency on serotonergic ASM constriction. The cholinergic response of extrapulmonary airways was not altered, whereas a considerable increase was observed in cav-3−/− intrapulmonary bronchi. Thus, cav-3 differentially organizes serotonergic and cholinergic signaling in ASM through mechanisms that are specific for airways of certain caliber and anatomical position. This may allow for selective and site-specific intervention in hyperreactive states.
Highlights
The mechanisms of controlling airway smooth muscle (ASM) tone are of utmost clinical importance since excessive sensitivity to contractile stimuli, called bronchial hyperresponsiveness (BHR), is considered as a hallmark in asthma and chronic obstructive pulmonary disease COPD1,2
Cav-3-immunolabelling was demonstrated in cardiac muscle cells in the heart that served as a positive control tissue (Fig. 1a)
Western blotting supported the immunohistochemical findings since the cav-3-antibody recognized a ≈20 kDa band in protein extracts from different tissues only in cav-3+/+ mice while it did not label the band in protein extracts from cav-3−/− mice (Fig. 1e)
Summary
The mechanisms of controlling airway smooth muscle (ASM) tone are of utmost clinical importance since excessive sensitivity to contractile stimuli, called bronchial hyperresponsiveness (BHR), is considered as a hallmark in asthma and chronic obstructive pulmonary disease COPD1,2. It was previously suggested that both, serotonergic and cholinergic signaling in ASM are orchestrated by specialized plasma membrane domains termed caveolae[13] These are cholesterol-rich, flask-shaped membrane invaginations that concentrate numerous receptor kinases, structural proteins, G-protein-coupled receptors (GPCR) and ion channels. We previously observed an about 50% decrease in muscarinic bronchonconstriction in MCD-treated PCLS while the muscarinic response was unaffected in intrapulmonary bronchi from cav-1−/− mice[12], consistent with an undisturbed cholinergic tracheal constriction in these mice[29] These data imply that additional constituents of cholesterol-rich microdomains, rather than cav-1 alone, are essential for receptor-mediated ASM constriction, with varying contributions depending on airway caliber and anatomical position. Such eNOS/cav-3 interaction is assumed to hold a key role in cholinergic modulation of cardiac myocyte function[32]
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