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 curren ts by serotonin was investigated with a two-electrode voltage clamp te chnique in Xenopus oocytes injected with rat brain RNA. After a 1-min application of 200 nM serotonin a transient potentiation of the NMDA r eceptor-mediated ion currents was observed. The serotonin-induced enha ncement was mimicked by the protein kinase C activators 1-oleoyl-2-ace tyl-sn-glycerol (100 mu M) and phorbol 12-myristate 13-acetate (10 nM) , whereas the inactive phorbol ester 4-alpha-phorbol 12-myristate 13-a cetate (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 se rotonin effect was inhibited by the protein kinase C inhibitors sphing osine (1 mu M) or staurosporine (1 mu M) added 20 min before NMDA appl ication and by oocyte injection of protein kinase C (PKC)inhibitor pep tide (500 ng/oocyte) 1 hr prior to recordings. The serotonin receptor involved was identified as a 5-HT2 receptor subtype by the finding tha t 200 nM of the selective 5-HT2 receptor agonist or-methyl-5-hydroxytr yptamine mimicked the potentiation of NMDA-induced ion currents by ser otonin, Furthermore, the observed potentiation was significantly reduc ed by coapplication of serotonin with 100 mu M of the selective 5-HT2 receptor antagonist ketanserin, These results indicate that 5-HT2 rece ptors enhance NMDA receptor function via phosphoinositol hydrolysis an d subsequent stimulation of PKC. (C) 1996 Wiley-Liss, Inc.