A homozygous 1–base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese

Fuchs, Sigrid; Nakazawa, Makoto; Maw, Marion A.; Tamai, Makoto; Oguchi, Yoshihisa; Gal, Andreas

doi:10.1038/ng0795-360

Cited by 256 publications

(149 citation statements)

References 18 publications

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“…Mutations in both the rhodopsin kinase (GRK1) gene (19) and the retinal arrestin (20) gene lead to Oguchi disease, a form of stationary night blindness caused by the prolonged activity of photoactivated rhodopsin. In the Drosophila system, inactivation of arrestin leads to the degeneration of the photoreceptor cells in a lightdependent manner (21), and in the well studied ␤-adrenergic system, overexpression of an inhibitor of GRKs 2 and 3 (␤-adrenergic receptor kinases 1 and 2) in a heart-specific manner, leads to an increased contractile response to ␤-agonist stimulation in transgenic mice (22).…”

Section: Discussionmentioning

confidence: 99%

G Protein-coupled Receptor Kinase 3 (GRK3) Gene Disruption Leads to Loss of Odorant Receptor Desensitization

Peppel¹,

Boekhoff²,

McDonald³

et al. 1997

Journal of Biological Chemistry

149

115

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G protein-coupled receptor kinases (GRKs) 2 and 3 (␤-adrenergic receptor kinases 1 and 2 (␤ARK1 and -2)) mediate the agonist-dependent phosphorylation and uncoupling of many G protein-coupled receptors. These two members of the GRK family share a high degree of sequence homology and show overlapping patterns of substrate specificity in vitro. To define their physiological roles in vivo we have generated mice that carry targeted disruption of these genes. In contrast to GRK2-deficient mice, which die in utero (Jaber, M., Koch, W. J., Rockman, H., Smith, B., Bond, R. A., Sulik, K. K., Ross, J. JR., Lefkowitz, R. J. Caron, M. G., and Giros, B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 12974 -12979), GRK3 deletion allows for normal embryonic and postnatal development. GRK3 is expressed to a high degree in the olfactory epithelium, where GRK2 is absent. Here we report that cilia preparations derived from GRK3-deficient mice lack the fast agonist-induced desensitization normally seen after odorant stimulation. Moreover, total second messenger (cAMP) generation in these cilia preparations following odorant stimulation is markedly reduced when compared with preparations from wildtype littermates. This reduction in the ability to generate cAMP is evident even in the presence of nonodorant receptor stimuli (GTP␥S and forskolin), suggesting a compensatory dampening of the G protein-adenylyl cyclase system in the GRK3 (؊/؊) mice in the olfactory epithelium. These findings demonstrate the requirement of GRK3 for odorant-induced desensitization of cAMP responses.Many G protein-coupled receptors (GPCRs) 1 show diminished ability to signal and couple to G proteins after prolonged or repeated agonist stimulation. This phenomenon, referred to as agonist-mediated desensitization, occurs very rapidly and is initiated via receptor phosphorylation by G protein-coupled receptor kinases (GRKs) that serve to uncouple the receptor from its G protein (1).Whereas the function of these proteins has been mostly studied in vitro and in tissue culture the physiological relevance of the mechanisms initiated by them have just begun to be explored. While there is some evidence of substrate specificity among the different members of the GRK family, most show activity toward a wide variety of agonist-occupied receptors in vitro. This, in addition to their ubiquitous tissue expression, has made it difficult to precisely determine the role of the GRKs in vivo. To clarify the physiological role of the individual members of this family, we have generated mice that carry targeted disruptions of the GRK2 or GRK3 (␤ARK2) genes. GRK2 deletion is embryonically lethal as homozygous mice die in utero before gestational day 15.5 of severe cardiac malformations (2). Whereas GRKs 2 and 3 show 81% amino acid identity (3) and an overlapping pattern of tissue expression (4), GRK3 apparently is not able to compensate for the loss of GRK2 in embryogenesis. In most tissues examined GRK2 is the predominant form. However, in the olfactory epithelium GRK2 is virtually a...

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Section: Discussionmentioning

confidence: 99%

G Protein-coupled Receptor Kinase 3 (GRK3) Gene Disruption Leads to Loss of Odorant Receptor Desensitization

Peppel¹,

Boekhoff²,

McDonald³

et al. 1997

Journal of Biological Chemistry

149

115

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“…Mutations of the genes for Drosophila arrestins cause a defect in the ability of the animal to inactivate meta-rhodopsin, and after 5 days of light\dark exposure result in retinal degeneration [113]. The importance of arrestins in humans is indicated by the finding that a homozygous 1 bp deletion in the arrestin gene is a frequent cause of Oguchi disease, a congenital form of night blindness [114].…”

Section: Role Of Arrestins In Receptor Desensitizationmentioning

confidence: 99%

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Böhm

Grady

Bunnett

1997

Biochemical Journal

476

322

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The large and functionally diverse group of G-protein-coupled receptors includes receptors for many different signalling molecules, including peptide and non-peptide hormones and neurotransmitters, chemokines, prostanoids and proteinases. Their principal function is to transmit information about the extracellular environment to the interior of the cell by interacting with the heterotrimeric G-proteins, and they thereby participate in many aspects of regulation. Cellular responses to agonists of these receptors are usually rapidly attenuated. Mechanisms of signal attenuation include removal of agonists from the extracellular fluid, receptor desensitization, endocytosis and downregulation. Agonists are removed by dilution, uptake by transporters and enzymic degradation. Receptor desensitization is mediated by receptor phosphorylation by G-protein receptor kinases and second-messenger kinases, interaction of phosphorylated receptors with arrestins and receptor uncoupling from

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“…Well-known examples of such genes include rhodopsin and peripherin [I,2]. Recently, S-antigen or retinal arrestin, which plays a role in desensitization of photoactivated rhodopsin in phototransduction [3], joined the ranks of retinal genes that can cause retinopathy; a mutation in this gene was shown to be involved in Oguchi disease, a form of congenital stationary night blindness [4].…”

Section: Introductionmentioning

confidence: 99%

Immunolocalization of X‐arrestin in human cone photoreceptors

et al. 1996

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X.arrestia is a recently identified retina-specific gene of unknown function. Affinity-purified anti-peptide antibody to human X-arrestin was prepared, and used in Western blot analysis of human retinal proteins and for immunohistoichemistry on human retinal sections. By Western blot analysis, the antibody specifically bound to an -47 kDa protein, and by indirect immunofluoresicenice specifiically labeled cone photoreceptors with greatest intensity in their outer segments. In single and double label experiments, the loicalization of X-arrestin immunoreaictivity was compared with immunolabeling patterns obtained with antibodies to red/green cone opsin, rhodopsin, and S.antigen. The results showed that X-arrestin is expressed in red-, green, and blue-sensitive cones in the human retina.

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A homozygous 1–base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese

Cited by 256 publications

References 18 publications

G Protein-coupled Receptor Kinase 3 (GRK3) Gene Disruption Leads to Loss of Odorant Receptor Desensitization

G Protein-coupled Receptor Kinase 3 (GRK3) Gene Disruption Leads to Loss of Odorant Receptor Desensitization

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Immunolocalization of X‐arrestin in human cone photoreceptors

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