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Cristy Ann Ku, Aaron Coyner, Renee C Ryals, Shreya Datta, Yuquan Wen, Mark E Pennesi; The role of ERK1/2 activation in serotonin-receptor mediated protection against light-induced retinopathy.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4389. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling mediates cell surface receptor signaling through sequential protein kinase cascades that affect a multitude of downstream substrates. Its effects have been contrastingly implicated in cell survival and cell death, and its role in retinal degeneration remains unclear. We examine ERK1/2 signaling following treatment with 5-HT receptor modulators, previously shown to confer photoreceptor cell survival following light-induced retinopathy. Specifically, we examine effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an 5-HT1A agonist, and ketanserin and sarpogrelate, two 5-HT2A receptor antagonists.
Albino BALB/c mice received intraperitoneal delivery of 5-HT receptor modulators, 8-OH-DPAT, ketanserin, sarpogrelate, or vehicle control immediately before 10K lux light exposure. ERK1/2 activation in the retina was assessed after 20 min of light exposure, and from 0 to 48 hours after 1 hr of light damage, through western blot quantification of phosphorylated ERK1/2. To evaluate the neuroprotective effect of ERK1/2 activation conferred by 5-HT receptor modulators, we inhibited ERK1/2 phosphorylation with MEK inhibitor, PD0325901, prior to administration of the 5-HT drugs. Spectral-domain optical coherence tomography (SD-OCT; Biotigen, Inc.) and electroretinography (ERG) was conducted to examine retinal structure and function as measures of neuroprotection, following treatment with 5-HT receptor modulators with and without MEK inhibitor. Retinal thickness was quantified on manually segmented images in IGOR Pro.
5-HT1A agonists and 5-HT2A antagonists showed distinct temporal inhibition and activation of ERK1/2, which was significantly different from vehicle control (p<0.05). Antagonists showed an early decreased ERK1/2 phosphorylation, and late increased ERK1/2 activation. Inhibition of ERK1/2 phosphorylation with MEK inhibitors mitigated the protective effects of 5-HT receptor modulators as assessed through OCT and ERG.
Serotonin G-protein coupled receptor (GPCR) signaling involves activation of the MAPK pathway in the retina. ERK1/2 signaling appears to play a role in the protective effects mediated by 5-HT1A agonists and 5-HT2A antagonists. Future studies will elucidate the downstream anti-apoptotic and cell survival pathways subsequent to ERK1/2 activation.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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