دورية أكاديمية
Determination of structural domains for G protein coupling and ligand binding in beta 3-adrenergic receptor.
| العنوان: | Determination of structural domains for G protein coupling and ligand binding in beta 3-adrenergic receptor. |
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| المؤلفون: | Guan XM; Department of Molecular Pharmacology and Biochemistry, Merck Research Labs, Rahway, New Jersey 07065, USA., Amend A, Strader CD |
| المصدر: | Molecular pharmacology [Mol Pharmacol] 1995 Sep; Vol. 48 (3), pp. 492-8. |
| نوع المنشور: | Comparative Study; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print Cited Medium: Print ISSN: 0026-895X (Print) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics |
| مواضيع طبية MeSH: | GTP-Binding Proteins/*metabolism , Receptors, Adrenergic, beta/*metabolism, Adrenergic beta-Agonists/metabolism ; Adrenergic beta-Agonists/pharmacology ; Amino Acid Sequence ; Base Sequence ; Binding, Competitive ; Cell Membrane/metabolism ; Cell Membrane/ultrastructure ; Ethanolamines/metabolism ; Ethanolamines/pharmacology ; Humans ; Iodine Radioisotopes ; Iodocyanopindolol ; Ligands ; Molecular Sequence Data ; Pindolol/analogs & derivatives ; Pindolol/metabolism ; Pindolol/pharmacology ; Protein Conformation ; Receptors, Adrenergic, beta-3 |
| مستخلص: | The beta 3-adrenergic receptor (beta 3AR) is a member of the super-family of G protein-coupled receptors that are characterized by seven putative transmembrane helices connected by hydrophilic loops. The mechanism by which the activated beta ARs transmit the signals across the plasma membrane involves the stimulation of Gs, which in turn activates adenylyl cyclase, yielding the second messenger cAMP. In the present study, we created a series of mutant beta 3ARs to explore the structural basis for the subtype-specific binding of BRL 37344, a beta 3-selective agonist, and for the coupling of the receptor to Gs. To study the mechanism of subtype-specific binding of BRL 37344, chimeric beta 2/beta 3ARs were constructed and expressed in Raji cells. Binding studies suggest that the transmembrane segment 5 region of the beta 3AR contains critical determinants for observed high affinity for BRL 37344. Previous studies of beta 2ARs have demonstrated a role for the third intracellular loop in activating Gs. To investigate the role of this region in the beta 3AR, we constructed mutant beta 3ARs lacking a small segment of the amino- or carboxyl-terminal domain of the third intracellular loop. Expression of these mutant receptors in mouse L cells and Raji cells reveals that although both mutants are capable of binding the antagonist [125l]iodocyanopindolol, the agonist-stimulated cAMP production mediated by these mutant receptors is markedly attenuated or abolished. In addition, both mutant beta 3ARs exhibit an approximately 10-fold increase in affinity for agonist binding, whereas the affinity for antagonists is not affected. This increased agonist affinity is not altered by treatment with 100 microM 5' quanylyl-imidodiphosphate, suggesting that these mutant receptors are uncoupled from G proteins. The results of the present study demonstrate that these regions of the third intracellular loop of beta 3AR are critical for coupling to G proteins and suggest a role for these regions in maintaining the resting state of the unliganded receptor. |
| المشرفين على المادة: | 0 (Adrenergic beta-Agonists) 0 (Ethanolamines) 0 (Iodine Radioisotopes) 0 (Ligands) 0 (Receptors, Adrenergic, beta) 0 (Receptors, Adrenergic, beta-3) 5DZZ1926YW (BRL 37344) 83498-72-0 (Iodocyanopindolol) BJ4HF6IU1D (Pindolol) EC 3.6.1.- (GTP-Binding Proteins) |
| تواريخ الأحداث: | Date Created: 19950901 Date Completed: 19951030 Latest Revision: 20171116 |
| رمز التحديث: | 20221213 |
| PMID: | 7565630 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 0026-895X |
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