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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In the present study we investigated the modulation of hypothalamic NMDA receptor-mediated currents by cyclic AMP-dependent protein kinase (PKA) using the two-electrode voltage-clamp technique in Xenopus oocytes injected with rat hypothalamic mRNA. Application of forskolin, which activates PKA by means of cyclic AMP stimulation, caused a transient increase of NMDA-induced currents, whereas the inactive forskolin analogue 1,9-dideoxyforskolin had no effect. Incubation of oocytes with a membrane-permeable analogue of cyclic AMP, 8-bromoadenosine 3′,5′ -cyclic monophosphate, potentiated NMDA responses even more prominently than with forskolin. NMDA-induced currents recorded from Xenopus oocytes injected with cRNA encoding the NMDA receptor subunits NR1, NR2A, and/or NR2B, mainly found in rat hypothalamus, were not affected by PKA activation but were increased by protein kinase C (PKC) stimulation. It is interesting that inhibition of endogenous protein phosphatase 1 and/or 2A by calyculin A resulted in a similar enhancement of hypothalamic NMDA-induced currents. Preinjection of oocytes with calyculin A impeded the PKA- but not the PKC-mediated potentiation of hypothalamic NMDA-induced currents. We propose the involvement of an additional third messenger in the PKA effect, which acts most likely via the inhibition of tonically active protein phosphatase 1 and/or 2A.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : The aim of the present study was to identify theN-terminal regions of human corticotropin-releasing factor (CRF) receptor type1 (hCRF-R1) that are crucial for ligand binding. Mutant receptors wereconstructed by replacing specific residues in hCRF-R1 with amino acids fromthe corresponding position in the N-terminal region of the human vasoactiveintestinal peptide receptor type 2 (hVIP-R2). In cyclic AMP stimulation andCRF binding assays, it was established that two regions within the N-terminaldomain were crucial for the binding of CRF receptor agonists and antagonists :one region mapping to amino acids 43-50 and a second amino acid sequenceextending from position 76 to 84 of hCRF-R1. Recently, it was found that thelatter sequence plays a very important role in determining the high ligandselectivity of the Xenopus CRF-R1 (xCRF-R1). Replacement of aminoacids 76-84 of hCRF-R1 with residues from the same segment of the hVIP-R2 Nterminus markedly reduced the binding affinity of CRF ligands. Mutation ofArg76 or Asn81 but not Gly83 of hCRF-R1 to the corresponding amino acids of xCRF-R1 or hVIP-R2 resulted in 100-1,000-fold lower affinities for human/rat CRF, rat urocortin, and astressin. These data underline the importance of the N-terminal domain of CRF-R1 in high-affinity ligand binding.
    Type of Medium: Electronic Resource
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