The main goal of this proposal is to continue exploration of intracellular Ca2+-dependent mechanisms that regulate voltage- and ligand-gated channels, and light-induced postsynaptic responses in retinal ganglion cells. The important role of intracellular Ca2+, and Ca2+-activated neuroregulatory processes in modulating ion channels and synaptic responses in ganglion cells, has received considerable attention in recent years. Still, it is fair to say that the mechanisms, and impact of such modulation on signal processing by ganglion cells are little understood. In neurons, including those of retina, stimulation of Ca2+ influx is sufficient to reorganize the actin cytoskeleton, which in turn influences the activity of voltage-dependent ion channels and synaptic transmission. The experimental hypothesis of this proposal is that certain Ca-dependent modulatory processes triggered by intracellular Ca2+ elevation during repetitive synaptic activity, or by release from internal stores are mediated by changes in cytoskeletal organization, i.e. its polymerization/ depolymerization. To test this hypothesis the Ca2+-dependence of the actin cytoskeleton reorganization and its effect on voltage-activated K+ and Ca2+ currents will be studied using a combination of electrophysiological (whole-cell patch clamp), and histochemical methods. Further, the contribution of actin filaments to the regulation of light-induced postsynaptic responses in ganglion cells will be investigated. Cytoskeleton-related changes in intracellular Ca2+ accumulation through different pathways (e.g. voltage-activated channels, glutamate receptor channels, or release from internal stores) will be studied by Ca2+ imaging. An exploration of the functional relationship between Ca2+ and the cytoskeleton state will contribute to our understanding the physiological roles of the actin cytoskeleton in the regulation of Ca2+-dependent neuromodulatory processes as well as Ca2+ homeostasis. These processes underlie normal retinal function and their imbalance has been linked to pathophysiology of the retina.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Hunter, Chyren
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New York University
Schools of Medicine
New York
United States
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Xing, Wei; Akopian, Abram; Kri┼żaj, David (2012) Trafficking of presynaptic PMCA signaling complexes in mouse photoreceptors requires Cav1.4 ?1 subunits. Adv Exp Med Biol 723:739-44
Busquet, Perrine; Nguyen, Ngoc Khoi; Schmid, Eduard et al. (2010) CaV1.3 L-type Ca2+ channels modulate depression-like behaviour in mice independent of deaf phenotype. Int J Neuropsychopharmacol 13:499-513
Mizuno, Fengxia; Barabas, Peter; Krizaj, David et al. (2010) Glutamate-induced internalization of Ca(v)1.3 L-type Ca(2+) channels protects retinal neurons against excitotoxicity. J Physiol 588:953-66
Cristofanilli, Massimiliano; Mizuno, Fengxia; Akopian, Abram (2007) Disruption of actin cytoskeleton causes internalization of Ca(v)1.3 (alpha 1D) L-type calcium channels in salamander retinal neurons. Mol Vis 13:1496-507
Cristofanilli, Massimiliano; Akopian, Abram (2006) Calcium channel and glutamate receptor activities regulate actin organization in salamander retinal neurons. J Physiol 575:543-54
Akopian, A; Szikra, T; Cristofanilli, M et al. (2006) Glutamate-induced Ca2+ influx in third-order neurons of salamander retina is regulated by the actin cytoskeleton. Neuroscience 138:17-24
Schubert, T; Akopian, A (2004) Actin filaments regulate voltage-gated ion channels in salamander retinal ganglion cells. Neuroscience 125:583-90
Witkovsky, Paul; Veisenberger, Eleonora; Haycock, John W et al. (2004) Activity-dependent phosphorylation of tyrosine hydroxylase in dopaminergic neurons of the rat retina. J Neurosci 24:4242-9
Akopian, Abram (2003) Differential modulation of light-evoked on- and off-EPSCs by paired-pulse stimulation in salamander retinal ganglion cells. Brain Res 967:235-46
Akopian, Abram; Galoyan, Armen (2003) Effect of hypothalamic proline-rich-polypeptide on voltage-gated Ca2+ currents in retinal ganglion cells. Neurochem Res 28:1867-71

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