June 2013
Volume 54, Issue 15
ARVO Annual Meeting Abstract  |   June 2013
The synaptic clustering protein Vesl-1/Homer 1 mediates protection of retinal neurons
Author Affiliations & Notes
  • Peter Koulen
    Ophthalmology / Vision Research Center, University of Missouri-Kansas City, Kansas City, MO
  • Footnotes
    Commercial Relationships Peter Koulen, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 3263. doi:
  • Views
  • Share
  • Tools
    • Alerts
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Peter Koulen; The synaptic clustering protein Vesl-1/Homer 1 mediates protection of retinal neurons. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3263.

      Download citation file:

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

  • Supplements

Purpose: Optic neuropathies resulting in the acute or gradual loss of visual function share cell death of retinal ganglion cells (RGCs) as a defining characteristic. Specifically, loss of RGCs due to programmed cell death in degenerative retinopathies is preceded by L-Glutamate mediated excitotoxicity, subsequent intracellular calcium dyshomeostasis and calciotoxicity. The Vesl-1/Homer 1 (H1) protein, as a member of the Homer protein family of synaptic clustering proteins, controls the intracellular free calcium ion concentration by interaction with intracellular calcium release channels and their upstream G protein signaling cascades. The present study tested the hypothesis that modulation of the H1 protein concentration in RGCs leads to protection against excitotoxicity.

Methods: RGCs and retinal explants were isolated and cultured from adult C57BL/6J mice and cellular viability in response to chronic L-Glutamate-mediated toxicity was measured using RGC-specific immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. The concentration of H1 proteins in RGCs and organotypic cultures was modulated using H1 isoform-specific expression vectors and small interfering RNA and measured using microfluorimetry. Changes in the intracellular free calcium ion concentration were determined using calcium imaging and pharmacological stimulation of intracellular calcium release.

Results: Both the long and the short isoform of H1, Vesl-1L/Homer 1c (H1c) and Vesl-1S/Homer 1a (H1a), respectively, are expressed by RGCs. Overexpression of H1a increased RGC viability in both isolated cells and organotypic cultures by 37% and 46%, respectively. This was accompanied by attenuation of calcium release from inositol-1,4,5-trisphosphate (IP3)-sensitive stores by 29% and 38%, respectively. Overexpression of H1c or siRNA mediated knockdown of H1a resulted in increased calcium release and decreased RGC viability.

Conclusions: H1 isoforms differentially modulate the gain of intracellular calcium release allowing the control of cellular toxicity affecting intracellular calcium levels with H1a as a dominant-negative regulator generating RGC protection. This mechanism of action represents a novel target for therapeutic intervention in optic neuropathies.

Keywords: 439 calcium • 615 neuroprotection • 695 retinal degenerations: cell biology  

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.