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The Journal of Neuroscience, August 15, 2007, 27(33):8805-8815; doi:10.1523/JNEUROSCI.2751-07.2007

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Cellular/Molecular
Constitutive Excitation by Gly90Asp Rhodopsin Rescues Rods from Degeneration Caused by Elevated Production of cGMP in the Dark

Michael L. Woodruff,¹ Elena V. Olshevskaya,² Andrey B. Savchenko,² Igor V. Peshenko,² Ronald Barrett,³ Ronald A. Bush,⁴ Paul A. Sieving,⁴ Gordon L. Fain,^1,5 and Alexander M. Dizhoor²

¹Department of Physiological Science, University of California, Los Angeles, Los Angeles, California 90095, ²Hafter Research Laboratories, Pennsylvania College of Optometry, Elkins Park, Pennsylvania 19027, ³Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan 48202, ⁴National Institutes of Health, National Eye Institute, National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland 20892, and ⁵Jules Stein Eye Institute, University of California, Los Angeles School of Medicine, Los Angeles, California 90095

Correspondence should be addressed to Alexander M. Dizhoor, Hafter Research Laboratories, Pennsylvania College of Optometry, 8360 Old York Road, Elkins Park, PA 19027. Email: adizhoor{at}pco.edu

Previous experiments indicate that congenital human retinal degeneration caused by genetic mutations that change the Ca²⁺ sensitivity of retinal guanylyl cyclase (retGC) can result from an increase in concentration of free intracellular cGMP and Ca²⁺ in the photoreceptors. To rescue degeneration in transgenic mouse models having either the Y99C or E155G mutations of the retGC modulator guanylyl cyclase-activating protein 1 (GCAP-1), which produce elevated cGMP synthesis in the dark, we used the G90D rhodopsin mutation, which produces constitutive stimulation of cGMP hydrolysis. The effects of the G90D transgene were evaluated by measuring retGC activity biochemically, by recording single rod and electroretinogram (ERG) responses, by intracellular free Ca²⁺ measurement, and by retinal morphological analysis. Although the G90D rhodopsin did not alter the abnormal Ca²⁺ sensitivity of retGC in the double-mutant animals, the intracellular free cGMP and Ca²⁺ concentrations returned close to normal levels, consistent with constitutive activation of the phosphodiesterase PDE6 cascade in darkness. G90D decreased the light sensitivity of rods but spared them from severe retinal degeneration in Y99C and E155G GCAP-1 mice. More than half of the photoreceptors remained alive, appeared morphologically normal, and produced electrical responses, at the time when their siblings lacking the G90D rhodopsin transgene lost the entire retinal outer nuclear layer and no longer responded to illumination. These experiments indicate that mutations that lead to increases in cGMP and Ca²⁺ can trigger photoreceptor degeneration but that constitutive activation of the transduction cascade in these animals can greatly enhance cell survival.

Key words: rod; retina; degeneration; cGMP; GCAP; guanylyl cyclase; calcium

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Received Nov. 13, 2006; accepted June 26, 2007.

Correspondence should be addressed to Alexander M. Dizhoor, Hafter Research Laboratories, Pennsylvania College of Optometry, 8360 Old York Road, Elkins Park, PA 19027. Email: adizhoor{at}pco.edu

This article has been cited by other articles:

				I. V. Peshenko, E. V. Olshevskaya, and A. M. Dizhoor Binding of Guanylyl Cyclase Activating Protein 1 (GCAP1) to Retinal Guanylyl Cyclase (RetGC1): THE ROLE OF INDIVIDUAL EF-HANDS J. Biol. Chem., August 1, 2008; 283(31): 21747 - 21757. [Abstract] [Full Text] [PDF]

				M. L. Woodruff, K. M. Janisch, I. V. Peshenko, A. M. Dizhoor, S. H. Tsang, and G. L. Fain Modulation of Phosphodiesterase6 Turnoff during Background Illumination in Mouse Rod Photoreceptors J. Neurosci., February 27, 2008; 28(9): 2064 - 2074. [Abstract] [Full Text] [PDF]

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