The human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator

Dizhoor, Alexander M.; Lowe, David; Olshevskaya, Elena V.; Laura, Richard; Hurley, James B.

doi:10.1016/0896-6273(94)90449-9

Cited by 337 publications

(300 citation statements)

References 30 publications

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“…Because RD3 interacts with photoreceptor GCs, we first examined the distribution of GC1 and GC2 by confocal scanning microscopy. GC1 and GC2 localized to the outer segment layer of WT mouse retina, with GC1 expressed in both rod and cone outer segments and GC2 present only in rod outer segments, in agreement with previous reports (15)(16)(17)(18). In contrast, GC1 and GC2 immunostaining was undetectable in rods and cones of the rd3 mouse retina (Fig.…”

Section: Resultssupporting

confidence: 79%

RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells

Azadi

Molday

2010

Proc. Natl. Acad. Sci. U.S.A.

172

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Guanylate cyclases, GC1 and GC2, are localized in the light-sensitive outer segment compartment of photoreceptor cells, where they play a crucial role in phototransduction by catalyzing the synthesis of cGMP, the second messenger of phototransduction, and regulating intracellular Ca 2+ levels in combination with the cGMP-gated channel. Mutations in GC1 are known to cause Leber congenital amaurosis type 1 (LCA1), a childhood disease associated with severe vision loss. Although the enzymatic and regulatory properties of guanylate cyclases have been studied extensively, the molecular determinants responsible for their trafficking in photoreceptors remain unknown. Here we show that RD3, a protein of unknown function encoded by a gene associated with photoreceptor degeneration in humans with Leber congenital amaurosis type 12 (LCA12), the rd3 mouse, and rcd2 collie, colocalizes and interacts with GC1 and GC2 in rod and cone photoreceptor cells of normal mice. GC1 and GC2 are undetectable in photoreceptors of the rd3 mouse deficient in RD3 by immunofluorescence microscopy. Cell expression studies show that RD3 mediates the export of GC1 from the endoplasmic reticulum to endosomal vesicles, and that the C terminus of GC1 is required for RD3 binding. Our results indicate that photoreceptor degeneration in the rd3 mouse, rcd2 dog, and LCA12 patients is caused by impaired RD3-mediated guanylate cyclase expression and trafficking. The resulting deficiency in cGMP synthesis and the constitutive closure of cGMP-gated channels might cause a reduction in intracellular Ca 2+ to a level below that required for long-term photoreceptor cell survival. membrane trafficking | photoreceptor degeneration | vision | calcium homeostasis | retinal disease mechanisms

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Section: Resultssupporting

confidence: 79%

RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells

Azadi

Molday

2010

Proc. Natl. Acad. Sci. U.S.A.

172

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“…Also, a naturally occurring point mutation (13) affects the two proteins differently (14,15). The ability of GCAPs to regulate RetGC in a Ca 2ϩ -sensitive manner is well established (7,10,11,16). However, specific structures within GCAPs that are responsible for regulating RetGCs have not yet been clearly defined.…”

mentioning

confidence: 99%

Mapping Sites in Guanylyl Cyclase Activating Protein-1 Required for Regulation of Photoreceptor Membrane Guanylyl Cyclases

Krylov

Niemi

Dizhoor

et al. 1999

Journal of Biological Chemistry

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Guanylyl cyclase activating protein (GCAP)-. The region between EF-hands 1 and 3 of GCAP-1 also contains elements needed for activation of RetGC. Finally, we found that inhibition of RetGC requires the first 9 amino-terminal residues of GCAP-1, but none of the residues from Gln 33 to the COOH-terminal Gly 205 are specifically required for inhibition. The ability of GCAP-1 mutants to regulate RetGC was tested on total guanylyl cyclase activity present in rod outer segments. In addition, the key mutants were also shown to produce similar effects on recombinant bovine outer segment cyclases GC1 and GC2.

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“…NCS proteins interact with and regulate many different physiological targets. Recoverin binds specifically and regulates rhodopsin kinase (23), whereas the guanylate cyclase activator proteins specifically regulate retinal guanylate cyclases (39,40). NCS-1 and yeast Frq1 activate phosphatidylinositol 4-kinase important for secretion from the Golgi (28).…”

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confidence: 99%

Neuronal Calcium Sensor-1 (Ncs1p) Is Up-regulated by Calcineurin to Promote Ca2+ Tolerance in Fission Yeast

Hamasaki-Katagiri

Ames

2010

Journal of Biological Chemistry

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) regulates signaling processes in the fission yeast, Schizosaccharomyces pombe (reviewed in Refs. 1-3), as it does in mammalian cells (reviewed in Ref. 4). Fission yeast contains ion channels (5, 6) and transporters (7-9) homologous to those involved in regulating Ca 2ϩ entry and signal transduction in excitable cells. Thus, stimulation of yeast cells by pheromones or other extracellular stimuli lead to an increase in intracellular Ca 2ϩ levels (10, 11) sensed by Ca 2ϩ -binding proteins belonging to the EF-hand superfamily (12). In S. pombe, a total of 23 genes specifies EF-hand-containing Ca 2ϩ -binding proteins, including cam1 (calmodulin) (13), cnb1 (calcineurin B) (14), and the recently characterized ncs1 gene (Ncs1p) (15), belonging to the neuronal calcium sensor (NCS) 2 family (16) expressed mostly in the central nervous system (17, 18).The primary sequence of S. pombe Ncs1p is Ͼ50% identical to neuronal homologs of the NCS branch of the EF-hand superfamily (19,20). Recoverin, the most intensively studied NCS protein, serves as a Ca 2ϩ sensor in retinal rod and cone cells where it controls the desensitization of rhodopsin (21-24). The NCS family also includes neuronal Ca 2ϩ sensors such as neurocalcin (25), hippocalcin (26), and frequenin (27), as well as the budding yeast homolog, Frq1 (28). All members of the NCS family have around 200 amino acid residues, contain N-terminal myristoylation, and possess four EF-hands.Three-dimensional structures are now known for many NCS proteins, including recoverin (29, 30), frequenin (31), Frq1 (32), neurocalcin (33), and guanylate cyclase activator proteins (34, 35). The Ca 2ϩ -bound forms of these proteins all share a common fold with four EF-hands arranged in a tandem array, with an exposed N-terminal myristoyl group. Binding of Ca 2ϩ to recoverin leads to extrusion of its myristoyl group such that many hydrophobic residues become exposed for target recognition (30, 36). The Ca 2ϩ -induced exposure of the myristoyl group, termed the Ca 2ϩ -myristoyl switch, enables recoverin to bind to membrane targets only at high Ca 2ϩ levels (37, 38). NCS proteins interact with and regulate many different physiological targets. Recoverin binds specifically and regulates rhodopsin kinase (23), whereas the guanylate cyclase activator proteins specifically regulate retinal guanylate cyclases (39, 40). NCS-1 and yeast Frq1 activate phosphatidylinositol 4-kinase important for secretion from the Golgi (28). Hippocalcin and VILIP proteins regulate guanylate cyclase and nicotinamide acetylcholine receptors implicated in synaptic plasticity (41). KChIPs (42), hippocalcin (43), and NCS-1 (44) all bind and regulate various ion channels and thus serve as Ca 2ϩ sensors that control membrane excitability. The mechanism of target regulation in each case is not understood, and it remains unclear how the structurally similar NCS proteins are able to specifically bind and regulate so many different target proteins.Yeast genetics is a powerful tool for dissecting NCS protein interactions in signa...

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The human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator

Cited by 337 publications

References 30 publications

RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells

RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells

Mapping Sites in Guanylyl Cyclase Activating Protein-1 Required for Regulation of Photoreceptor Membrane Guanylyl Cyclases

Neuronal Calcium Sensor-1 (Ncs1p) Is Up-regulated by Calcineurin to Promote Ca2+ Tolerance in Fission Yeast

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