Acute 5-HT7 receptor activation increases NMDA-evoked currents and differentially alters NMDA receptor subunit phosphorylation and trafficking in hippocampal neurons

Maryam S Vasefi,Michael F Jackson,Kai Yang,Jerry Li,John J Heikkila,Jeff S Kruk,John F Macdonald,Michael A Beazely

doi:10.1186/1756-6606-6-24

Abstract

BackgroundN-methyl-D-aspartate (NMDA) receptors are regulated by several G protein-coupled receptors (GPCRs) as well as receptor tyrosine kinases. Serotonin (5-HT) type 7 receptors are expressed throughout the brain including the thalamus and hippocampus. Long-term (2–24 h) activation of 5-HT7 receptors promotes the expression of neuroprotective growth factor receptors, including the platelet-derived growth factor (PDGF) β receptors which can protect neurons against NMDA-induced neurotoxicity.ResultsIn contrast to long-term activation of 5-HT7 receptors, acute (5 min) treatment of isolated hippocampal neurons with the 5-HT7 receptor agonist 5-carboxamidotryptamine (5-CT) enhances NMDA-evoked peak currents and this increase in peak currents is blocked by the 5-HT7 receptor antagonist, SB 269970. In hippocampal slices, acute 5-HT7 receptor activation increases NR1 NMDA receptor subunit phosphorylation and differentially alters the phosphorylation state of the NR2B and NR2A 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.ConclusionsIn contrast to the negative 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 highlight the potential for temporally differential regulation of NMDA receptors by the 5-HT7 receptor.

Highlights

N-methyl-D-aspartate (NMDA) receptors are regulated by several G protein-coupled receptors (GPCRs) as well as receptor tyrosine kinases
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
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

Summary

Introduction

N-methyl-D-aspartate (NMDA) receptors are regulated by several G protein-coupled receptors (GPCRs) as well as receptor tyrosine kinases. Serotonin (5-HT) type 7 receptors are expressed throughout the brain including the thalamus and hippocampus. In isolated cortical neurons, activation of 5-HT1A receptors inhibits NMDA receptor currents [4] and 5-HT3 receptor activation. 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 (See figure on previous page.) Figure 1 5-HT7 receptor activation increases NMDA-evoked currents in isolated hippocampal neurons. A) 50 nM 5-CT was applied to isolated CA1 hippocampal neurons for 5 min beginning at min 5 after a stable baseline of NMDA-evoked currents was established (closed circles). In samples treated with the 5-HT7 receptor antagonist, SB 269970 (1 μM) was included in the bath and was present before, during, and after 5-CT application. C) 5-HT7 antagonist SB269970 prevents the enhancement of INMDA by 5-CT. ** Indicates p < 0.01, one-way ANOVA (Turkey’s post hoc comparison)

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Conclusion