QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, July 7, 2004, 24(27):6078-6085; doi:10.1523/JNEUROSCI.0963-04.2004

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by Olshevskaya, E. V. Articles by Dizhoor, A. M. Search for Related Content PubMed PubMed Citation Articles by Olshevskaya, E. V. Articles by Dizhoor, A. M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL

 Previous Article  |  Next Article 

Neurobiology of Disease
The Y99C Mutation in Guanylyl Cyclase-Activating Protein 1 Increases Intracellular Ca²⁺ and Causes Photoreceptor Degeneration in Transgenic Mice

Elena V. Olshevskaya,^1 * Peter D. Calvert,^2 * Michael L. Woodruff,^3 * Igor V. Peshenko,¹ Andrey B. Savchenko,¹ Clint L. Makino,² Ye-Shih Ho,⁵ Gordon L. Fain,^3,4 and Alexander M. Dizhoor¹

¹Hafter Research Laboratories, Pennsylvania College of Optometry, Elkins Park, Pennsylvania 19027, ²Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, ³Department of Physiological Science and ⁴Jules Stein Eye Institute, University of California at Los Angeles, Los Angeles, California 90095, and ⁵Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan 48202

Guanylyl cyclase-activating proteins (GCAPs) are Ca²⁺-binding proteins that activate guanylyl cyclase when free Ca²⁺ concentrations in retinal rods and cones fall after illumination and inhibit the cyclase when free Ca²⁺ reaches its resting level in the dark. Several forms of retinal dystrophy are caused by mutations in GUCA1A, the gene coding for GCAP1. To investigate the cellular mechanisms affected by the diseased state, we created transgenic mice that express GCAP1 with a Tyr99Cys substitution (Y99C GCAP1) found in human patients with a late-onset retinal dystrophy (Payne et al., 1998). Y99C GCAP1 shifted the Ca²⁺ sensitivity of the guanylyl cyclase in photoreceptors, keeping it partially active at 250 nM free Ca²⁺, the normal resting Ca²⁺ concentration in darkness. The enhanced activity of the cyclase in the dark increased cyclic nucleotide-gated channel activity and elevated the rod outer segment Ca²⁺ concentration in darkness, measured by using fluo-5F and laser spot microscopy. In different lines of transgenic mice the magnitude of this effect rose with the Y99C GCAP1 expression. Surprisingly, there was little change in the rod photoresponse, indicating that dynamic Ca²⁺-dependent regulation of cGMP synthesis was preserved. However, the photoreceptors in these mice degenerated, and the rate of the cell loss increased with the level of the transgene expression, unlike in transgenic mice that overexpressed normal GCAP1. These results provide the first direct evidence that a mutation linked to congenital blindness increases Ca²⁺ in the outer segment, which may trigger the apoptotic process.

Key words: retina; guanylyl cyclase; calcium; retinal dystrophy; transgenic mice; cone; retinal degeneration; photoreceptors

---

Received March 15, 2004; revised May 24, 2004; accepted May 25, 2004.

This article has been cited by other articles:

				A. M. Dizhoor, M. L. Woodruff, E. V. Olshevskaya, M. C. Cilluffo, M. C. Cornwall, P. A. Sieving, and G. L. Fain Night Blindness and the Mechanism of Constitutive Signaling of Mutant G90D Rhodopsin J. Neurosci., November 5, 2008; 28(45): 11662 - 11672. [Abstract] [Full Text] [PDF]

				R. J. Davis, J. Tosi, K. M. Janisch, J. M. Kasanuki, N.-K. Wang, J. Kong, I. Tsui, M. Cilluffo, M. L. Woodruff, G. L. Fain, et al. Functional Rescue of Degenerating Photoreceptors in Mice Homozygous for a Hypomorphic cGMP Phosphodiesterase 6 b Allele (Pde6bH620Q) Invest. Ophthalmol. Vis. Sci., November 1, 2008; 49(11): 5067 - 5076. [Abstract] [Full Text] [PDF]

				C. L. Makino, I. V. Peshenko, X.-H. Wen, E. V. Olshevskaya, R. Barrett, and A. M. Dizhoor A Role for GCAP2 in Regulating the Photoresponse: GUANYLYL CYCLASE ACTIVATION AND ROD ELECTROPHYSIOLOGY IN GUCA1B KNOCK-OUT MICE J. Biol. Chem., October 24, 2008; 283(43): 29135 - 29143. [Abstract] [Full Text] [PDF]

				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]

				M. L. Woodruff, E. V. Olshevskaya, A. B. Savchenko, I. V. Peshenko, R. Barrett, R. A. Bush, P. A. Sieving, G. L. Fain, and A. M. Dizhoor Constitutive Excitation by Gly90Asp Rhodopsin Rescues Rods from Degeneration Caused by Elevated Production of cGMP in the Dark J. Neurosci., August 15, 2007; 27(33): 8805 - 8815. [Abstract] [Full Text] [PDF]

				I. V. Peshenko and A. M. Dizhoor Activation and Inhibition of Photoreceptor Guanylyl Cyclase by Guanylyl Cyclase Activating Protein 1 (GCAP-1): THE FUNCTIONAL ROLE OF Mg2+/Ca2+ EXCHANGE IN EF-HAND DOMAINS J. Biol. Chem., July 27, 2007; 282(30): 21645 - 21652. [Abstract] [Full Text] [PDF]

				A. F. X. Goldberg, L. M. Ritter, N. Khattree, N. S. Peachey, R. N. Fariss, L. Dang, M. Yu, and A. R. Bottrell An Intramembrane Glutamic Acid Governs Peripherin/rds Function for Photoreceptor Disk Morphogenesis Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 2975 - 2986. [Abstract] [Full Text] [PDF]

				I. V. Peshenko and A. M. Dizhoor Ca2+ and Mg2+ Binding Properties of GCAP-1: EVIDENCE THAT Mg2+-BOUND FORM IS THE PHYSIOLOGICAL ACTIVATOR OF PHOTORECEPTOR GUANYLYL CYCLASE J. Biol. Chem., August 18, 2006; 281(33): 23830 - 23841. [Abstract] [Full Text] [PDF]

				C. L. Makino, X.-H. Wen, N. Michaud, I. V. Peshenko, B. Pawlyk, R. S. Brush, M. Soloviev, X. Liu, M. L. Woodruff, P. D. Calvert, et al. Effects of Low AIPL1 Expression on Phototransduction in Rods Invest. Ophthalmol. Vis. Sci., May 1, 2006; 47(5): 2185 - 2194. [Abstract] [Full Text] [PDF]

				S. M. Hauck, P. A. R. Ekstrom, P. Ahuja-Jensen, S. Suppmann, F. Paquet-Durand, T. van Veen, and M. Ueffing Differential Modification of Phosducin Protein in Degenerating rd1 Retina Is Associated with Constitutively Active Ca2+/Calmodulin Kinase II in Rod Outer Segments Mol. Cell. Proteomics, February 1, 2006; 5(2): 324 - 336. [Abstract] [Full Text] [PDF]

				I. Sokal, W. J. Dupps, M. A. Grassi, J. Brown Jr, L. M. Affatigato, N. Roychowdhury, L. Yang, S. Filipek, K. Palczewski, E. M. Stone, et al. A Novel GCAP1 Missense Mutation (L151F) in a Large Family with Autosomal Dominant Cone-Rod Dystrophy (adCORD) Invest. Ophthalmol. Vis. Sci., April 1, 2005; 46(4): 1124 - 1132. [Abstract] [Full Text] [PDF]

				X. Liu, O. V. Bulgakov, X.-H. Wen, M. L. Woodruff, B. Pawlyk, J. Yang, G. L. Fain, M. A. Sandberg, C. L. Makino, and T. Li From the Cover: AIPL1, the protein that is defective in Leber congenital amaurosis, is essential for the biosynthesis of retinal rod cGMP phosphodiesterase PNAS, September 21, 2004; 101(38): 13903 - 13908. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help