Agonist-Promoted Homologous Desensitization of Human Airway Smooth Muscle Bitter Taste Receptors
| العنوان: | Agonist-Promoted Homologous Desensitization of Human Airway Smooth Muscle Bitter Taste Receptors |
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| المؤلفون: | Kathryn S. Robinett, Deepak A. Deshpande, Molly M. Malone, Stephen B. Liggett |
| المصدر: | American Journal of Respiratory Cell and Molecular Biology. 45:1069-1074 |
| بيانات النشر: | American Thoracic Society, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Dynamins, Pulmonary and Respiratory Medicine, Agonist, medicine.medical_specialty, Arrestins, medicine.drug_class, medicine.medical_treatment, Molecular Sequence Data, Myocytes, Smooth Muscle, Clinical Biochemistry, Bronchi, Tachyphylaxis, Biology, Cell Line, Receptors, G-Protein-Coupled, Saccharin, Homologous desensitization, Internal medicine, medicine, Animals, Humans, Myocyte, Amino Acid Sequence, Enzyme Inhibitors, Receptor, Molecular Biology, Protein Kinase C, beta-Arrestins, Desensitization (medicine), Quinine, Beta-Arrestins, Hydrazones, Articles, Cell Biology, Membrane hyperpolarization, G-Protein-Coupled Receptor Kinases, Cyclic AMP-Dependent Protein Kinases, Bronchodilator Agents, Endocrinology, Calcium |
| الوصف: | Bitter taste receptors (TAS2Rs) were shown to be expressed in human airway smooth muscle (ASM). They couple to specialized [Ca(2+)](i) release, leading to membrane hyperpolarization, the relaxation of ASM, and marked bronchodilation. TAS2Rs are G-protein-coupled receptors, known to undergo rapid agonist-promoted desensitization that can limit therapeutic efficacy. Because TAS2Rs represent a new drug target for treating obstructive lung disease, we investigated their capacity for rapid desensitization, and assessed their potential mechanisms. The pretreatment of human ASM cells with the prototypic TAS2R agonist quinine resulted in a 31% ± 5.1% desensitization of the [Ca(2+)](i) response from a subsequent exposure to quinine. No significant change in the endothelin-stimulated [Ca(2+)](i) response was attributed to the short-term use of quinine, indicating a homologous form of desensitization. The TAS2R agonist saccharin also evoked desensitization, and cross-compound desensitization with quinine was evident. Desensitization of the [Ca(2+)](i) response was attenuated by a dynamin inhibitor, suggesting that receptor internalization (a G-protein coupled receptor kinase [GRK]-mediated, β-arrestin-mediated process) plays an integral role in the desensitization of TAS2R. Desensitization was insensitive to antagonists of the second messenger kinases protein kinase A and protein kinase C. Using intact airways, short-term, agonist-promoted TAS2R desensitization of the relaxation response was also observed. Thus these receptors, which represent a potential novel target for direct bronchodilators, undergo a modest degree of agonist-promoted desensitization that may affect clinical efficacy. Collectively, the results of these mechanistic studies, along with the multiple serines and threonines in intracellular loop 3 and the cytoplasmic tail of TAS2Rs, suggest a GRK-mediated mode of desensitization. |
| تدمد: | 1535-4989 1044-1549 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::72c9aa17edbeeeee88f2e2c8f2cffa1f https://doi.org/10.1165/rcmb.2011-0061oc |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....72c9aa17edbeeeee88f2e2c8f2cffa1f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15354989 10441549 |
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