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Novel functions of photoreceptor guanylate cyclases revealed by targeted deletion

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Abstract

Targeted deletion of membrane guanylate cyclases (GCs) has yielded new information concerning their function. Here, we summarize briefly recent results of laboratory generated non-photoreceptor GC knockouts characterized by complex phenotypes affecting the vasculature, heart, brain, kidney, and other tissues. The main emphasis of the review, however, addresses the two GCs expressed in retinal photoreceptors, termed GC-E and GC-F. Naturally occurring GC-E (GUCY2D) null alleles in human and chicken are associated with an early onset blinding disorder, termed “Leber congenital amaurosis type 1” (LCA-1), characterized by extinguished scotopic and photopic ERGs, and retina degeneration. In mouse, a GC-E null genotype produces a recessive cone dystrophy, while rods remain functional. Rod function is supported by the presence of GC-F (Gucy2f), a close relative of GC-E. Deletion of Gucy2f has very little effect on rod and cone physiology and survival. However, a GC-E/GC-F double knockout (GCdko) phenotypically resembles human LCA-1 with extinguished ERGs and rod/cone degeneration. In GCdko rods, PDE6 and GCAPs are absent in outer segments. In contrast, GC-E−/− cones lack proteins of the entire phototransduction cascade. These results suggest that GC-E may participate in transport of peripheral membrane proteins from the endoplasmic reticulum (ER) to the outer segments.

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Abbreviations

ER:

Endoplasmic reticulum

GC:

Guanylate cyclase

GCdko:

GC-E/GC-F double knockout

GCAP:

Guanylate cyclase-activating protein

LCA:

Leber congenital amaurosis

PDE6:

cGMP-specific photoreceptor phosphodiesterase

TGN:

trans-Golgi network

WT:

Wild-type

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Acknowledgments

This study was supported by RO1 EY08123, RO1 EY019298, P30 EY014800 and a Center Grant from the Foundation Fighting Blindness.

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  1. Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Science Center, 65 Mario Capecchi Dr., Salt Lake City, UT, 84132, USA

    Sukanya Karan, Jeanne M. Frederick & Wolfgang Baehr

  2. Department of Biology, University of Utah, Salt Lake City, UT, 84112, USA

    Sukanya Karan & Wolfgang Baehr

  3. Department of Neurobiology and Anatomy, University of Utah Health Science Center, Salt Lake City, UT, 84132, USA

    Wolfgang Baehr

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  1. Sukanya Karan
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  2. Jeanne M. Frederick
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  3. Wolfgang Baehr
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Correspondence to Wolfgang Baehr.

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Karan, S., Frederick, J.M. & Baehr, W. Novel functions of photoreceptor guanylate cyclases revealed by targeted deletion. Mol Cell Biochem 334, 141–155 (2010). https://doi.org/10.1007/s11010-009-0322-z

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  • DOI: https://doi.org/10.1007/s11010-009-0322-z

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