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J Biol Chem, Vol. 273, Issue 28, 17311-17314, July 10, 1998

COMMUNICATION
Constitutive Activation of Photoreceptor Guanylate Cyclase by Y99C Mutant of GCAP-1
POSSIBLE ROLE IN CAUSING HUMAN AUTOSOMAL DOMINANT CONE DEGENERATION

Alexander M. Dizhoor^§, Sergei G. Boikov, and Elena V. Olshevskaya

From the  Department of Ophthalmology/Kresge Eye Institute and ^§ Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201

Photoreceptor membrane guanylate cyclases (RetGC) are regulated by calcium-binding proteins, GCAP-1 and GCAP-2. At Ca²⁺ concentrations below 100 nM, characteristic of light-adapted photoreceptors, guanylate cyclase-activating protein (GCAPs) activate RetGC, and at free Ca²⁺ concentrations above 500 nM, characteristic of dark-adapted photoreceptors, GCAPs inhibit RetGC. A mutation, Y99C, in human GCAP-1 was recently found to be linked to autosomal dominant cone dystrophy in a British family (Payne, A. M., Downes, S. M., Bessant, D. A. R., Taylor, R., Holder, G. E., Warren, M. J., Bird, A. C., and Bhattachraya, S. S. (1998) Hum. Mol. Genet. 7, 273-277). We produced recombinant Y99C GCAP-1 mutant and tested its ability to activate RetGC in vitro at various free Ca²⁺ concentrations. The Y99C mutation does not decrease the ability of GCAP-1 to activate RetGC. However, RetGC stimulated by the Y99C GCAP-1 remains active even at Ca²⁺ concentration above 1 µM. Hence, the cyclase becomes constitutively active within the whole physiologically relevant range of free Ca²⁺ concentrations. We have also found that the Y99C GCAP-1 can activate RetGC even in the presence of Ca²⁺-loaded nonmutant GCAPs. This is consistent with the fact that cone degeneration was dominant in human patients who carried such mutation (Payne, A. M., Downes, S. M., Bessant, D. A. R., Taylor, R., Holder, G. E., Warren, M. J., Bird, A. C., and Bhattachraya, S. S. (1998) Hum. Mol. Genet. 7, 273-277). A similar mutation, Y104C, in GCAP-2 results in a different phenotype. This mutation apparently does not affect Ca²⁺ sensitivity of GCAP-2. Instead, the Y104C GCAP-2 stimulates RetGC less efficiently than the wild-type GCAP-2. Our data indicate that cone degeneration associated with the Y99C mutation in GCAP-1 can be a result of constitutive activation of cGMP synthesis.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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