June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Homer 1 protein isoforms differentially control the intracellular calcium signaling and viability of retinal neurons
Author Affiliations & Notes
  • Peter Koulen
    Ophthal/Vision Research Ctr, University of Missouri-Kansas City, Kansas City, Missouri, United States
    Basic Medical Science, University of Missouri – Kansas City, School of Medicine, Kansas City, Missouri, United States
  • Footnotes
    Commercial Relationships   Peter Koulen, None
  • Footnotes
    Support  NIH: EY014227, EY022774, AG010485, AG022550, AG027956, RR022570, RR027093; Felix and Carmen Sabates Missouri Endowed Chair in Vision Research; Challenge Grant from Research to Prevent Blindness; Vision Research Foundation of Kansas City
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1748. doi:
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      Peter Koulen; Homer 1 protein isoforms differentially control the intracellular calcium signaling and viability of retinal neurons. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1748.

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

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Abstract

Purpose : Vision loss in optic neuropathies is characterized by the degeneration of retinal ganglion cells (RGCs). Cell death of RGCs is preceded by L-glutamate mediated excitotoxicity, subsequent cellular calcium dyshomeostasis and calcium toxicity. Control of these signaling pathways is the target of therapy development efforts. Homer proteins, in addition to their function as synaptic clustering proteins, control the intracellular free calcium ion concentration by interaction with intracellular calcium release channels. The present study tested the hypothesis that Homer 1 protein isoforms differentially control intracellular calcium signaling in RGCs and thereby affect RGC viability.

Methods : Murine RGCs were isolated and cultured. The concentration of Homer 1 protein isoforms in RGCs was altered using isoform-specific mammalian expression vectors and small interfering RNA and determined with microfluorimetry. Changes in intracellular calcium signaling were measured using calcium imaging and pharmacological control of intracellular calcium channel activity, as well as single channel electrophysiology of intracellular calcium release channels. RGC viability and changes in expression levels of Homer 1 protein isoforms were measured in response to chronic L-glutamate-mediated toxicity using cytochemical methods.

Results : RGCs express long and short isoforms of Homer 1. Expression levels change in response to chronic L-glutamate toxicity towards a higher prevalence of the short isoform when compared to vehicle controls (p<0.01). Knockdown of the short isoform significantly (p<0.001) reduced viability of RGCs by 56%, whereas knockdown of the long isoform significantly (p<0.01) increased the viability of RGCs by 49%. This was paralleled by statistically significantly (p<0.01) potentiated or attenuated calcium release from intracellular stores, respectively. Overexpression of individual isoforms had the reverse effect on calcium release from intracellular stores and viability of RGCs.

Conclusions : Isoforms of Homer 1 control calcium release from intracellular stores differentially and thereby affect cellular viability of RGCs in an isoform-specific manner as a function of cellular calcium dyshomeostasis resulting from disease processes. These mechanisms of action therefore represent novel potential targets for therapeutic intervention and drug development in optic neuropathies.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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