Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation

Nishiguchi, Koji M.; Sandberg, Michael A.; Kooijman, Aart C.; Martemyanov, Kirill A.; Pott, Jan Willem R.; Hagstrom, Stephanie A.; Arshavsky, Vadim Y.; Berson, Eliot L.; Dryja, Thaddeus P.

doi:10.1038/nature02170

Cited by 156 publications

(115 citation statements)

References 24 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…The physiological significance of RGS9-1 interaction with R9AP was emphasized in a recent human study of patients bearing defects in either RGS9 or R9AP molecules (9). The mutations of either protein resulted in a clinical phenotype characterized by impaired ability to adjust to bright light and by impaired temporal resolution of the visual signals resulting in reduced ability to see moving objects.…”

Section: Rgsmentioning

confidence: 99%

R7BP, a Novel Neuronal Protein Interacting with RGS Proteins of the R7 Family

Martemyanov

Yoo

Skiba

et al. 2005

Journal of Biological Chemistry

Self Cite

136

192

View full text Add to dashboard Cite

The R7 subfamily of the regulators of G protein signaling (RGS) proteins is represented by four members broadly expressed in the mammalian nervous system. Here we report that in the brain all four R7 proteins form tight complexes with a previously unidentified protein, which we call the R7-binding protein or R7BP. We initially identified R7BP as a protein co-precipitating with the R7 protein, RGS9, from extracts obtained from the striatal region of the brain. We further showed that R7BP forms a tight complex with RGS9 in vitro and that this binding occurs via the N-terminal DEP domain of RGS9. R7BP is expressed throughout the entire central nervous system but not in any of the tested nonneuronal tissues. All four R7 RGS proteins co-precipitate with R7BP from brain extracts and recombinant R7 proteins bind recombinant R7BP with high efficiency. The closest homolog of R7BP is R9AP which was previously found to interact with RGS9 in photoreceptors. Both R7BP and R9AP are related to the syntaxin subfamily of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in vesicular trafficking and exocytosis. In photoreceptors R9AP regulates several critical properties of RGS9 including its intracellular targeting, stability and catalytic activity. This suggests that R7BP interactions with R7 proteins in the brain may also bear major functional significance. RGS1 proteins regulate the duration of G protein signaling by stimulating the rate of the GTP hydrolysis on G protein ␣ subunits (reviewed in Refs. 1 and 2). RGS proteins are classified in six to nine subfamilies based on the homology within the RGS catalytic domain (1-3). Most RGS proteins contain additional noncatalytic domains that modulate the properties of their catalytic domains and allow them to interact with their partners in a broad range of signaling pathways. The R7 (also called "C") subfamily of RGS proteins contains four members expressed in the mammalian nervous system, RGS6, RGS7, RGS9, and RGS11 (reviewed in Ref. 4). R7 proteins share common domain composition and exist as constitutive complexes with the type 5 G protein ␤ subunit (G␤5).Marked progress in the understanding of the function of the R7 protein came from the studies of the short splice variant of RGS9, RGS9-1, which regulates signal duration in the phototransduction pathway in vertebrate rod and cone photoreceptors. Several functional properties of RGS9-1 in photoreceptors are regulated by its interacting partner, a SNARE-like protein R9AP. R9AP is responsible for targeting RGS9-1 to the photoreceptor outer segment, an intracellular compartment where phototransduction takes place (5). It also determines the RGS9-1 expression level by protecting RGS9-1 from proteolytic degradation in the cell (6). Finally, R9AP enhances the ability of RGS9-1 to stimulate G protein GTPase activity thus allowing the visual signal to be terminated on the physiologically rapid time scale (5,7,8). RGS9-1 interaction with R9AP is mediated by the N-terminal domain of RGS9-1 c...

show abstract

Section: Rgsmentioning

confidence: 99%

R7BP, a Novel Neuronal Protein Interacting with RGS Proteins of the R7 Family

Martemyanov

Yoo

Skiba

et al. 2005

Journal of Biological Chemistry

Self Cite

136

192

View full text Add to dashboard Cite

show abstract

“…Our data suggest a deficit in episodic-like/working memory; however, visual perception data from human RGS9 mutants suggest that RGS9 mice may have visual deficits relating to luminance change accommodation (Nishiguchi et al, 2004). To assess whether visual deficits confounded the DMTP working memory results of the RGS9 KO mice, we tested the mice in the visible platform version of the water maze.…”

Section: Abnormal Episodic-like/working Memory In Rgs9 Ko Micementioning

confidence: 99%

Motor coordination deficits in mice lacking RGS9

et al. 2008

View full text Add to dashboard Cite

RGS9-2 is a striatum-enriched protein that negatively modulates dopamine and opioid receptor signaling. We examined the role of RGS9-2 in modulating complex behavior. Genetic deletion of RGS9-2 does not lead to global impairments, but results in selective abnormalities in certain behavioral domains. RGS9 knockout (KO) mice have decreased motor coordination on the accelerating rotarod and deficits in working memory as measured in the delayed-match to place version of the water maze. In contrast, RGS9 KO mice exhibit normal locomotor activity, anxietylike behavior, cue and contextual fear conditioning, startle threshold, and pre-pulse inhibition. These studies are the first to describe a role for RGS9-2 in motor coordination and working memory and implicate RGS9-2 as a potential therapeutic target for motor and cognitive dysfunction. KeywordsRGS9; motor coordination; working memory; delayed-match to place water maze; dopamine; striatum IntroductionThe regulators of G protein signaling (RGS) family of proteins negatively modulate heterotrimeric G protein signaling by stimulating the GTPase activity of G protein α subunits (Berman and Gilman, 1998) and can function as effector molecules in certain signaling networks (De Vries et al., 2000). RGS proteins also regulate cellular excitability via their indirect modulation of G-protein-coupled inwardly rectifying K+ channels (GIRK) and voltage-dependent calcium channels (Berman et al., 1996;Chuang et al., 1998;Doupnik et al., 1997;Hollinger and Hepler, 2002;Sondek and Siderovski, 2001;Zhou et al., 2000).The greater than 25 mammalian RGS proteins identified to date are defined by their 120 amino acid RGS domain and can be organized into subfamilies based on structural features and relative specificity for different G-protein subunits (Traynor and Neubig, 2005). Numerous RGS genes are expressed in brain with highly region-specific expression patterns (Dohlman and Thorner, 1997). The biological role of specific RGS proteins is currently an area of active research.

show abstract

“…The RGS9-1 knockout shows prolonged visual potentials (7), and RGS9-2 disruption results in markedly enhanced responses to drugs of abuse, such as cocaine, amphetamines, and opiates (56,71). A human disorder, bradyopsia, with reduced visual acuity for rapidly moving objects, has been identified with loss of RGS9-1 or its membrane anchor (54). The RGS2 knockout was initially reported to have only subtle behavioral and immunologic phenotypes but was subsequently found to be markedly hypertensive (33).…”

mentioning

confidence: 99%

Pleiotropic Phenotype of a Genomic Knock-In of an RGS-Insensitive G184S Gnai2 Allele

Huang

Charbeneau

et al. 2006

Molecular and Cellular Biology

101

View full text Add to dashboard Cite

Signal transduction via guanine nucleotide binding proteins (G proteins) is involved in cardiovascular, neural, endocrine, and immune cell function. Regulators of G protein signaling (RGS proteins) speed the turn-off of G protein signals and inhibit signal transduction, but the in vivo roles of RGS proteins remain poorly defined. To overcome the redundancy of RGS functions and reveal the total contribution of RGS regulation at the G␣ i2 subunit, we prepared a genomic knock-in of the RGS-insensitive G184S Gnai2 allele. The G␣ i2 G184S knock-in mice show a dramatic and complex phenotype affecting multiple organ systems (heart, myeloid, skeletal, and central nervous system). Both homozygotes and heterozygotes demonstrate reduced viability and decreased body weight. Other phenotypes include shortened long bones, a markedly enlarged spleen, elevated neutrophil counts, an enlarged heart, and behavioral hyperactivity. Heterozygous G␣ i2 ؉/G184S mice show some but not all of these abnormalities. Thus, loss of RGS actions at G␣ i2 produces a dramatic and pleiotropic phenotype which is more evident than the phenotype seen for individual RGS protein knockouts.Cell-cell communication is fundamental to the maintenance of homeostasis. The G protein-coupled receptor superfamily is arguably the most abundant and diverse protein family in cellular signaling and is tightly regulated. A novel family of Ͼ20 proteins termed regulators of G protein signaling, or RGS proteins, both tonically inhibit G protein function and also serve as signal control points (2,22,34,39,69). RGS-mediated inhibition of G protein signaling occurs through direct binding of the RGS protein to the G␣ subunit, with subsequent GTPase-accelerating protein (GAP) actions to rapidly deactivate G␣ (2). Deactivation may be accelerated up to 1,000-fold and shuts down both G␣ and G␤␥ signals (42, 48). RGS proteins may also competitively inhibit G␣ binding to effectors such as phospholipase C (32). Most of the currently known RGS proteins interact with either Gi or Gq family G proteins and influence cyclic AMP (cAMP), Ca 2ϩ , mitogen-activated protein kinase, and ion channel signaling. There is strong evidence implicating them in the subsecond kinetics of G i -and G o -mediated ion channel activation and deactivation in the heart (10, 21, 36) and neurons (36). In addition, the conserved RGS domain has been found to serve as a multifunctional protein adapter which can recruit many effectors or regulators to the vicinity of activated G proteins (31,53,62). Notable examples include p115rhoGEF (30, 40) and GRK2 (44). There is also emerging interest in RGS proteins as drug targets (9,20,53,72).However, the physiological functions of RGS proteins remain poorly defined. A number of RGS knockouts have been reported (for example, RGS1, -2, -4, and -9). The RGS9-1 knockout shows prolonged visual potentials (7), and RGS9-2 disruption results in markedly enhanced responses to drugs of abuse, such as cocaine, amphetamines, and opiates (56, 71). A human disorder, bradyopsia, with r...

show abstract

Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation

Cited by 156 publications

References 24 publications

R7BP, a Novel Neuronal Protein Interacting with RGS Proteins of the R7 Family

R7BP, a Novel Neuronal Protein Interacting with RGS Proteins of the R7 Family

Motor coordination deficits in mice lacking RGS9

Pleiotropic Phenotype of a Genomic Knock-In of an RGS-Insensitive G184S Gnai2 Allele

Contact Info

Product

Resources

About