Keshavarz, M.M.KeshavarzSkill, M.M.SkillHollenhorst, M. I.M. I.HollenhorstMaxeiner, S.S.MaxeinerWalecki, M.M.WaleckiPfeil, U.U.PfeilKummer, W.W.KummerKrasteva-Christ, G.G.Krasteva-Christ2022-11-182019-05-152022-11-182018http://nbn-resolving.de/urn:nbn:de:hebis:26-opus-145667https://jlupub.ub.uni-giessen.de/handle/jlupub/9407http://dx.doi.org/10.22029/jlupub-8795The 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-3â -/- 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.enNamensnennung 4.0 Internationalddc:610