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J. Biol. Chem., Vol. 282, Issue 12, 8837-8847, March 23, 2007

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The Function of Guanylate Cyclase 1 and Guanylate Cyclase 2 in Rod and Cone Photoreceptors^*

Wolfgang Baehr^¶1, Sukanya Karan, Tadao Maeda^||, Dong-Gen Luo^**, Sha Li, J. Darin Bronson, Carl B. Watt, King-Wai Yau^**, Jeanne M. Frederick, and Krzysztof Palczewski^||

From the Departments of Ophthalmology and Visual Sciences, Biology, and ^¶Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah 84112, the ^||Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, and the ^**Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Retinal guanylate cyclases 1 and 2 (GC1 and GC2) are responsible for synthesis of cyclic GMP in rods and cones, but their individual contributions to phototransduction are unknown. We report here that the deletion of both GC1 and GC2 rendered rod and cone photoreceptors nonfunctional and unstable. In the rod outer segments of GC double knock-out mice, guanylate cyclase-activating proteins 1 and 2, and cyclic GMP phosphodiesterase were undetectable, although rhodopsin and transducin -subunit were mostly unaffected. Outer segment membranes of GC1^–/– and GC double knock-out cones were destabilized and devoid of cone transducin (- and -subunits), cone phosphodiesterase, and G protein-coupled receptor kinase 1, whereas cone pigments were present at reduced levels. Real time reverse transcription-PCR analyses demonstrated normal RNA transcript levels for the down-regulated proteins, indicating that down-regulation is posttranslational. We interpret these results to demonstrate an intrinsic requirement of GCs for stability and/or transport of a set of membrane-associated phototransduction proteins.

Received for publication, November 7, 2006 , and in revised form, January 23, 2007.

^* This work was supported by National Institutes of Health Grants EY09339 and P30 EY11373 (to K. P.), EY08123 and P30 EY014800 (to W. B.), and EY06837 (to K. W. Y.); a grant from Research to Prevent Blindness, Inc. (to the Departments of Ophthalmology at the University of Utah), and a Center grant of the Foundation Fighting Blindness, Inc. (Owings Mills, MD) (to the University of Utah). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This paper is dedicated to the memory of Kimberly A. Howes (1956–2007).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1–S4.

¹ To whom correspondence should be addressed: Moran Eye Center, University of Utah Health Science Center, 65 N. Medical Dr., Salt Lake City, UT 84132-5330. Tel.: 801-585-6643; Fax: 801-585-1515; E-mail: wbaehr{at}hsc.utah.edu.

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