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  • 1
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Organometallics 14 (1995), S. 3762-3767 
    ISSN: 1520-6041
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1520-6041
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Internalization and recycling of G protein-coupled receptors (GPCRs), such as the μ-opioid receptor, largely depend on agonist stimulation, whereas certain other receptor types recycle constitutively, e.g., the transferrin receptor. To investigate structural domains involved in μ-opioid receptor internalization, we constructed two truncation mutants bracketing a Ser/Thr-rich domain (354ThrSerSerThrIleGluGlnGlnAsn362) unique to the C-terminus of the μ-opioid receptor (mutants Trunc354 and Trunc363). Ligand binding did not differ substantially, and G protein coupling was slightly lower for these μ-receptor constructs, in particular for Trunc363. To permit localization of the receptor by immunocytochemistry, an epitope tag was added to the N-terminus of the wildtype and mutant receptors. Both the wild-type μ-opioid receptor and Trunc363 resided largely at the plasma membrane and internalized into vesicles upon stimulation with the agonist [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin. Internalization occurred into vesicles that contain transferrin receptors, as shown previously, as well as clathrin, but not caveolin. In contrast, even without any agonist present, Trunc354 colocalized in intracellular vesicles with clathrin and transferrin receptors, but not caveolin. On blocking internalization by hyperosmolar sucrose or acid treatment, Trunc354 translocated to the plasma membrane, indicating that the mutant internalized into clathrin-coated vesicles and recycled constitutively. Despite agonist-independent internalization of Trunc354, basal G protein coupling was not elevated, suggesting distinct mechanisms for coupling and internalization. Furthermore, a portion of the C-terminus, particularly the Ser/Thr domain, appears to suppress μ-receptor internalization, which can be overcome by agonist stimulation. These results demonstrate that a mutant GPCR can be constructed such that internalization, normally an agonist-dependent process, can occur spontaneously without concomitant G protein activation.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Human m1 muscarinic acetylcholine receptor mutants were screened to determine receptor domains and cellular pathways relevant to down-regulation. Mutations in the second intracellular loop and the junctions of the third intracellular loop of the receptor, where a role for receptor activation or internalization had been previously demonstrated in HEK293 cells, were selected for this study. To assess receptor down-regulation, the m1 receptor mutants were transfected into Chinese hamster ovary cells. Because receptor internalization is expected to precede down-regulation, mutants displaying intact internalization were selected to permit interpretation of mutational effects on down-regulation alone. Four mutations were identified that specifically impaired down-regulation without altering receptor internalization: V127A, I211A, E360A, and K362A. The results define new receptor domains in the second intracellular loop and the junctions of the third intracellular loop that are involved in down-regulation. These same four mutants were also defective in signaling via the phospholipase C and the adenylyl cyclase pathways and in G protein activation, as measured by [35S]GTPγS binding. However, the level of second messenger stimulation correlated poorly with the extent of down-regulation. In summary, several mutations of the m1 receptor selectively affect down-regulation, demonstrating that internalization and down-regulation represent distinct events driven by different cellular mechanisms.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-2568
    Keywords: COLLOIDAL BISMUTH SUBCITRATE ; CHEMICAL STRUCTURE ; HELICOBACTER PYLORI ; EXPERIMENTAL GASTRIC ULCER
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The recognition of the role of Helicobacterpylori in the pathogenesis of peptic ulcer disease hasled to renewed interest in bismuth pharmacology sincebismuth compounds have both anti-Helicobacter pylori and ulcer healing properties. The precisechemical structure of current bismuth compounds is notknown. This has hindered the development of new andpotentially more efficacious formulations. We havecreated two new compounds,2-chloro1,3-dithia-2-bismolane (CDTB) and1,2-[bis(1,3-dithia-2-bismolane)thio]ethane (BTBT), withknown structure. In a rat model of gastric ulceration,BTBT was comparable to, and CDTB was significantly less effective thancolloidal bismuth subcitrate in healing cryoprobeinducedulcers. However, both BTBT and CDTB inhibited H. pylorigrowth in vitro at concentrations 〈1/10 that of colloidal bismuth subcitrate. The effects onulcer healing are not mediated by suppression of acidsecretion, pepsin inhibition, or prostaglandinproduction. Since all treated animals received the same amount of elemental bismuth, it appears thatthe efficacy of bismuth compounds varies with compoundstructure and is not simply dependent on the delivery ofbismuth ion. Because the structure of the novel compounds is known, our understanding of therelationship of bismuth compound structure and tobiologic activity will increase. In the future it may bepossible to design other novel bismuth compounds with more potent anti-H. pylori and ulcer healingeffects.
    Type of Medium: Electronic Resource
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