title: Modulation of hypothalamic NMDA receptor function by cyclic AMP-dependent protein kinase and phosphatases.
abstract: 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.
authors.affiliation: Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Goettingen, Germany. nijholt@mail.mpiem.gwdg.de
authors.forename: I
authors.initials: I
authors.lastname: Nijholt
authors.forename: T
authors.initials: T
authors.lastname: Blank
authors.forename: A
authors.initials: A
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Kügler
authors.forename: J
authors.initials: J
authors.lastname: Spiess
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008387:Marine Toxins; D016202:N-Methylaspartate / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D054645:Protein Phosphatase 1; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013449:Sulfonamides; D014982:Xenopus laevis
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D008387:Marine Toxins; D010080:Oxazoles; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D013449:Sulfonamides; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D016202:N-Methylaspartate; C059041:calyculin A; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide