Serotonin 5-HT2 receptor activation potentiates N-methyl-D-aspartate receptor-mediated ion currents by a protein kinase C-dependent mechanism.
Modulation of N-methyl-D-aspartate (NMDA) receptor-mediated ion currents by serotonin was investigated with a two-electrode voltage clamp technique in Xenopus oocytes injected with rat brain RNA. After a 1-min application of 200 nM serotonin a transient potentiation of the NMDA receptor-mediated ion currents was observed. The serotonin-induced enhancement was mimicked by the protein kinase C activators 1-oleoyl-2-acetyl-sn-glycerol (100 microM) and phorbol 12-myristate 13-acetate (10 nM), whereas the inactive phorbol ester 4-alpha-phorbol 12-myristate 13-acetate (10 nM) had no effect. From these observations it was concluded that protein kinase C was involved in the enhancement of NMDA-induced currents. In agreement with this conclusion, it was found that the serotonin effect was inhibited by the protein kinase C inhibitors sphingosine (1 microM) or staurosporine (1 microM) added 20 min before NMDA application and by oocyte injection of protein kinase C (PKC)-inhibitor peptide (500 ng/oocyte) 1 hr prior to recordings. The serotonin receptor involved was identified as a 5-HT2 receptor subtype by the finding that 200 nM of the selective 5-HT2 receptor agonist alpha-methyl-5-hydroxytryptamine mimicked the potentiation of NMDA-induced ion currents by serotonin. Furthermore, the observed potentiation was significantly reduced by co-application of serotonin with 100 microM of the selective 5-HT2 receptor antagonist ketanserin. These results indicate that 5-HT2 receptors enhance NMDA receptor function via phosphoinositol hydrolysis and subsequent stimulation of PKC.
Blank
T
T
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Göttingen, Germany.
Zwart
R
R
Nijholt
I
I
Spiess
J
J
D000818:Animals; D001921:Brain / Q000502:physiology*; D004075:Diglycerides / Q000494:pharmacology; D004789:Enzyme Activation; D005071:Evoked Potentials / Q000187:drug effects*; D005260:Female; D005998:Glycine / Q000494:pharmacology; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000502:physiology*; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014982:Xenopus laevis
D004075:Diglycerides; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D012701:Serotonin; D016202:N-Methylaspartate; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C; D008274:Magnesium; D013755:Tetradecanoylphorbol Acetate; D005998:Glycine