September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
The role of ERK1/2 activation in serotonin-receptor mediated protection against light-induced retinopathy.
Author Affiliations & Notes
  • Cristy Ann Ku
    Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States
  • Aaron Coyner
    Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States
  • Renee C Ryals
    Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States
  • Shreya Datta
    Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States
  • Yuquan Wen
    Baylor Visual Function Center, Baylor University Medical Center, Dallas, Texas, United States
  • Mark E Pennesi
    Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States
  • Footnotes
    Commercial Relationships   Cristy Ku, None; Aaron Coyner, None; Renee Ryals, None; Shreya Datta, None; Yuquan Wen, None; Mark Pennesi, Sucampo (C)
  • Footnotes
    Support  K08 EY021186, Career Development Award from Research to Prevent Blindness (New York, NY), CD-NMT-0914-0659-OHSU, Unrestricted Grant from Research to Prevent Blindness, Casey NIH Core Grant P30 EY 010572
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4389. doi:
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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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : 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.

Methods : 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.

Results : 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.

Conclusions : 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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