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Neuronal Calcium Sensors in Health and Disease

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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00474

Light-induced thiol oxidation of recoverin affects rhodopsin desensitization

 Evgeni Y. Zernii1, 2,  Aliya A. Nazipova3,  Ekaterina L. Nemashkalova3, Alexey S. Kazakov3, Olga S. Gancharova1, 2, Marina V. Serebryakova1,  Natalya K. Tikhomirova1,  Viktoriia E. Baksheeva1, Vasiliy I. Vladimirov4,  Dmitry V. Zinchenko4, Pavel P. Philippov1,  Ivan I. Senin1 and  Sergei E. Permyakov3*
  • 1Lomonosov Moscow State University, Russia
  • 2I.M. Sechenov First Moscow State Medical University, Russia
  • 3Institute for Biological Instrumentation (RAS), Russia
  • 4Institute of Bioorganic Chemistry (RAS), Russia

The excessive light illumination of mammalian retina is known to induce oxidative stress and photoreceptor cell death linked to progression of age-related macular degeneration. The photochemical damage of photoreceptors is suggested to occur via two apoptotic pathways that involve either excessive rhodopsin activation or constitutive phototransduction, depending on the light intensity. Both pathways are dramatically activated in the absence of rhodopsin desensitization by GRK1. Previously, we have shown that moderate illumination (halogen lamp, 1,500 lx, 1-5 h) of mammalian eyes provokes disulfide dimerization of recoverin, a calcium-dependent regulator of GRK1. Here, we demonstrate under in vivo conditions that both moderate long-term (metal halide lamp, 2,500 lx, 14 h, rat model) and intense short-term (halogen lamp, 30,000 lx for 3 h, rabbit model) illumination of the mammalian retina are accompanied by accumulation of disulfide dimer of recoverin. Furthermore, in the second case we reveal alternatively oxidized derivatives of the protein, apparently including its monomer with sulfinic group. Histological data indicate that thiol oxidation of recoverin precedes apoptosis of photoreceptors. Both disulfide dimer and oxidized monomer (or oxidation mimicking C39D mutant) of recoverin exhibit lowered α-helical content and thermal stability of their apo-forms, as well as increased Ca2+ affinity. Meanwhile, the oxidized monomer and C39D mutant of recoverin demonstrate impaired ability to bind photoreceptor membranes and regulate GRK1, whereas disulfide dimer exhibits notably improved membrane binding and GRK1 inhibition in absence of Ca2+. The latter effect is expected to slow down rhodopsin desensitization in the light, thereby favoring support of the light-induced oxidative stress, ultimately leading to photoreceptor apoptosis. Overall, the intensity and duration of illumination of the retina affect thiol oxidation of recoverin likely contributing to propagation of the oxidative stress and photoreceptor damage.

Keywords: Light-induced retinal damage, age-related macular degeneration, photoreceptor, Oxidative Stress, Apoptosis, Neuronal Calcium Sensor, Recoverin, Cysteine, Thiol oxidation, Disulfide dimerization, GRK1

Received: 27 Sep 2018; Accepted: 05 Dec 2018.

Edited by:

Daniele Dell'Orco, University of Verona, Italy

Reviewed by:

Pere Garriga, Universitat Politecnica de Catalunya, Spain
James Ames, University of California, Davis, United States  

Copyright: © 2018 Zernii, Nazipova, Nemashkalova, Kazakov, Gancharova, Serebryakova, Tikhomirova, Baksheeva, Vladimirov, Zinchenko, Philippov, Senin and Permyakov. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Sergei E. Permyakov, Institute for Biological Instrumentation (RAS), Pushchino, Russia,