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

Anshula Samarajeewa,Maryam S Vasefi,Nyasha Gondora,Michael A Beazely,John G Mielke,Lolita Goldemann,Chandni Khanderia,Nawaz Ahmed

doi:10.3389/fnbeh.2014.00391

Anshula Samarajeewa, Maryam S Vasefi + Show 6 more

Open Access

https://doi.org/10.3389/fnbeh.2014.00391

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Abstract

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.

Highlights

Neurotrophins, or neurotrophic factors, include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) (Skaper, 2012)
Given that tropomyosin-related kinase B (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 retinal ganglion cell (RGC) line 5 (RGC-5)
2 h ACTIVATION OF 5-HT7 RECEPTORS INCREASES TrkB EXPRESSION We investigated whether a shorter incubation of cortical neurons, SH-SY5Y or RGC-5 cells with LP 12 would result in similar changes in TrkB expression and phosphorylation

Summary

Introduction

Neurotrophins, or neurotrophic factors, include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) (Skaper, 2012). TrkB receptors are transmembrane receptor tyrosine kinases (RTKs) found in dendritic spines, axons and neuronal cell bodies. There are three TrkB isoforms, full-length TrkB (TrkB-FL), TrkB-Shc, and TrkB-T1, that all have the same extracellular ligand-binding domain and transmembrane domain, the T-Shc and TrkB-T1 receptors are truncated and lack tyrosine kinase activity found in TrkB-FL (Fenner, 2012). Both TrkB-T1 and TrkB-T-Shc receptors are thought to modulate TrkB-FL activity by forming. Increases in TrkB-T1 (via increased transcription, not as a degradation product of the full-length receptor) decrease TrkB-FL activity after excitotoxicity (Gomes et al, 2012)

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