Background N-methyl-D-aspartate (NMDA) receptors are regulated by several G protein-coupled receptors (GPCRs) as well as receptor tyrosine kinases. A66 subunits. NMDA receptor subunit cell surface expression is also differentially altered by 5-HT7 receptor agonists: NR2B cell surface expression is decreased whereas NR1 and NR2A surface expression are not significantly altered. Conclusions In contrast to the unfavorable regulatory effects of long-term activation of 5-HT7 receptors on NMDA receptor signaling acute activation of 5-HT7 receptors promotes NMDA receptor activity. These findings spotlight the potential for temporally differential regulation of NMDA receptors by the 5-HT7 receptor. oocytes 5 receptor activation increases NMDA receptor currents  and in prefrontal cortical slices 5 agonists enhance NMDA-evoked responses . A66 Although first identified in A66 the suprachiasmatic nucleus 5 receptors are expressed throughout the CNS including the hippocampus . The effect of 5-HT7 receptor ligands on NMDA-evoked currents remains unknown however recent studies A66 provide clear evidence for the regulation of glutamatergic signaling by 5-HT7 receptors. 5-HT7 receptors inhibit NMDA-induced neurotransmitter release in the dorsal raphe nucleus (DRN) and the physiological role of 5-HT7 receptors in circadian rhythms is usually associated with an inhibition of glutamate-dependent events [9 10 In the suprachiasmatic nucleus glutamate excitatory post-synaptic potentials (EPSPs) and glutamate-induced intracellular calcium levels are both inhibited by 5-HT7 receptor activation [11 12 Taken together these studies suggest that 5-HT7 receptor activation decreases NMDA and/or glutamate receptor signaling. In contrast compared to wild-type 5 receptor knock-out mice display a reduced induction of long-term potentiation (LTP) magnitude of LTP and hippocampus-associated learning . Therefore although there is usually evidence that 5-HT7 receptors negatively regulate NMDA/glutamate signaling deletion of 5-HT7 receptors decreased the magnitude of NMDA receptor-dependent events such as LTP. 5 receptors are Gαs-coupled although they may couple to additional Gα isoforms including Gα12[14 15 Recently we identified the 5-HT7 receptor as a A66 regulator of platelet-derived growth factor (PDGF) β receptor expression and activity . Activation of PDGFβ receptors by PDGF-BB selectively inhibits NR2B-containing NMDA receptor currents and this may be involved in the mechanism of PDGFβ receptor-mediated neuroprotection . Intriguingly 5 receptor-induced upregulation of the PDGFβ receptor was sufficient to protect neurons against NMDA-induced excitotoxicity . Thus we proposed that long-term activation of 5-HT7 receptors initiates pathways that ultimately negatively regulate NMDA receptor signaling. To clarify the direct effects of 5-HT7 receptor activation on NMDA receptor signaling we examined the effects of 5-HT7 receptor agonists and antagonists on NMDA-evoked currents NMDA receptor subunit phosphorylation and subunit cell surface expression in the hippocampus. In isolated hippocampal neurons application of the 5-HT7 receptor agonist 5 resulted in a rapid and sustained increase in peak NMDA-evoked currents. 5-HT7 receptor agonist treatment also differentially altered NMDA receptor subunit phosphorylation and cell surface expression. These data along with our previous work suggest a model for differential NMDA receptor regulation by 5-HT7 receptors over the short- and long-term. Results Application of the 5-HT7 receptor agonist 5 to isolated hippocampal neurons for 5?min increased NMDA-evoked peak currents (Physique?1). NMDA receptor currents were evoked once every 1?min using a 3?s exposure to NMDA (50?μM) and glycine (0.5?μM). 5-CT was applied in the bath constantly for 5?min after a 5-min stable baseline recording. This application increased NMDA-evoked currents to 142.5?±?7.4% (n?=?5) compared with baseline whereas NMDA-evoked currents in control cells were stable over the recording period (95.9?±?5.2% n?=?6) (p?0.01 one way ANOVA (Tukey’s post hoc comparison) Determine?1). Rabbit Polyclonal to OR2T2. The 5-CT-induced increase in NMDA-evoked currents was observed within minutes after 5-CT application and the increase in peak currents was sustained even after 5-CT was washed out (min 10 through 30). In addition to 5-HT7 5 also activates 5-HT1 and 5-HT5 receptors [19 20 However the A66 increase in NMDA-evoked currents by 5-CT was completely blocked by the 5-HT7 receptor-selective antagonist SB 269970 (Physique?1). Physique 1 5 receptor activation increases NMDA-evoked currents in isolated hippocampal.