[Control of bronchial contractility, regulation of receptor activity and expression].
Heptahelical receptors mediate contractile and relaxant responses of bronchial smooth muscle cells to mediators and drugs. The activity of these receptors is constitutively regulated through the equilibrium between their inactive conformation R and their active conformation R*, coupled to G proteins. This equilibrium is shifted to R* by agonists, with a relaxant response to beta-adrenergic agonists and a contractile response to muscarinic agonists. In contrast, inverse agonists shift this equilibrium to R with, for instance, a putative relaxant response to muscarinic inverse agonists. The expression of heptahelical receptors at the plasma membrane correspond to the equilibrium between the endocytosis of membrane receptors and the synthesis of receptor mRNA and protein. Endocytosis is activated by agonists and decreased by inverse agonists. The transcriptional regulation of heptahelical receptors in bronchial smooth muscle cells is tightly controlled by pro-inflammatory cytokines. The variety of the involved control pathways might explain the spasmogen-selective hyperresponsiveness, allowing a reappraisal of the dogma of non selective bronchial hyperresponsiveness in asthma.
Laboratoire de Neuroimmunopharmacologie, INSERM U 425, Faculté de Pharmacie, Université Louis Pasteur-Strasbourg, Illkirch.
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Landry
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Daeffler
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D001249:Asthma / Q000503:physiopathology; D001980:Bronchi / Q000502:physiology; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology*; D004705:Endocytosis; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D018121:Receptors, Cytokine / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics
D000318:Adrenergic beta-Agonists; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; D020962:Heterotrimeric GTP-Binding Proteins