Activation of 5-HT7 receptors increases neuronal platelet-derived growth factor β receptor expression

Vasefi, Maryam; Kruk, Jeff S.; Liu, Hui; Heikkila, John J.; Beazely, Michael A.

doi:10.1016/j.neulet.2012.01.016

Cited by 17 publications

(20 citation statements)

References 31 publications

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“…Conversely, there is evidence that 5-HT7 receptor agonists decrease glutamate-induced intracellular calcium release [11] and the amplitude of glutamate EPSPs [12]. Based on the findings reported here and our previous report describing the ability of long-term 5-HT7 receptor agonist treatment to upregulate PDGFβ receptors [16,18], we propose that the activation of 5-HT7 receptors may regulate NMDA receptor activity via two temporally distinct pathways (Figure 6): Acute (5 min) activation of 5-HT7 receptors increases NMDA-evoked currents whereas long-term (2–24 h) activation of 5-HT7 receptors upregulates PDGFβ receptors, a receptor tyrosine kinase that inhibits NMDA receptor activity [17,18,30]. …”

Section: Discussionmentioning

confidence: 57%

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

Vasefi¹,

Yang

Li³

et al. 2013

Mol Brain

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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.

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Section: Discussionmentioning

confidence: 57%

“…Recently we identified the 5-HT7 receptor as a regulator of platelet-derived growth factor (PDGF) β receptor expression and activity [16]. 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 [17].…”

Section: Introductionmentioning

confidence: 99%

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

Vasefi¹,

Yang

Li³

et al. 2013

Mol Brain

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“…The magnitude of activation of the PDGFβ receptor during transactivation (as measured by tyrosine phosphorylation) is typically much less than ligand-induced activation [10]. This may explain why ligand-induced activation results in rapid down-regulation of RTKs such as the PDGFβ receptor [9], whereas down-regulation of transactivated PDGFβ receptors has not been observed [10,17]. …”

Section: Introductionmentioning

confidence: 99%

Reactive Oxygen Species Are Required for 5-HT-Induced Transactivation of Neuronal Platelet-Derived Growth Factor and TrkB Receptors, but Not for ERK1/2 Activation

et al. 2013

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High concentrations of reactive oxygen species (ROS) induce cellular damage, however at lower concentrations ROS act as intracellular second messengers. In this study, we demonstrate that serotonin (5-HT) transactivates the platelet-derived growth factor (PDGF) type β receptor as well as the TrkB receptor in neuronal cultures and SH-SY5Y cells, and that the transactivation of both receptors is ROS-dependent. Exogenous application of H2O2 induced the phosphorylation of these receptors in a dose-dependent fashion, similar to that observed with 5-HT. However the same concentrations of H2O2 failed to increase ERK1/2 phosphorylation. Yet, the NADPH oxidase inhibitors diphenyleneiodonium chloride and apocynin blocked both 5-HT-induced PDGFβ receptor phosphorylation and ERK1/2 phosphorylation. The increases in PDGFβ receptor and ERK1/2 phosphorylation were also dependent on protein kinase C activity, likely acting upstream of NADPH oxidase. Additionally, although the ROS scavenger N-acetyl-l-cysteine abrogated 5-HT-induced PDGFβ and TrkB receptor transactivation, it was unable to prevent 5-HT-induced ERK1/2 phosphorylation. Thus, the divergence point for 5-HT-induced receptor tyrosine kinase (RTK) transactivation and ERK1/2 phosphorylation occurs at the level of NADPH oxidase in this system. The ability of 5-HT to induce the production of ROS resulting in transactivation of both PDGFβ and TrkB receptors may suggest that instead of a single GPCR to single RTK pathway, a less selective, more global RTK response to GPCR activation is occurring.

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“…Based on our previous work (Vasefi et al, 2012), and the literature identifying Gαs-coupled receptors and cyclic AMP pathways in regulating TrkB receptor expression (Ji et al, 2005; Heo et al, 2013), we predicted that 5-HT7 receptor activation would increase TrkB receptor levels via the Gαs-cyclic AMP-PKA pathway. However, 5-HT7 receptors are also reported to couple to Gα12 and Rho GTPase pathways, specifically the activation of RhoA and cdc42 (Kvachnina et al, 2005).…”

Section: Discussionmentioning

confidence: 97%

“…We have recently reported that long-term (24 h) application of 5-HT7 agonists (5-carboxamidotryptamine (5-CT) and LP 12) increases the expression of the platelet-derived growth factor (PDGF) β receptor in a PKA-dependent manner (Vasefi et al, 2012) and this increase in PDGF receptor expression was sufficient to protect primary hippocampal neurons against NMDA-induced excitotoxicity (Vasefi et al, 2013). Given that TrkB expression is regulated by several other Gαs-coupled receptors, we examined the ability of 5-HT7 agonists and antagonists to regulate TrkB receptor isoform expression and phosphorylation in primary mouse cerebral cortical cultures, the human neuroblastoma-derived SH-SY5Y cell line, and the RGC line 5 (RGC-5).…”

Section: Introductionmentioning

confidence: 99%

5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

Samarajeewa

Goldemann

Vasefi

et al. 2014

Front. Behav. Neurosci.

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The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the cortex and hippocampus. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF) receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA)-induced toxicity. The tropomyosin-related kinase B (TrkB) receptor is one of the receptors for brain-derived neurotrophic factor (BDNF) and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins toward the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands.

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Activation of 5-HT7 receptors increases neuronal platelet-derived growth factor β receptor expression

Cited by 17 publications

References 31 publications

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

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

Reactive Oxygen Species Are Required for 5-HT-Induced Transactivation of Neuronal Platelet-Derived Growth Factor and TrkB Receptors, but Not for ERK1/2 Activation

5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

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