Instability of GGL domain-containing RGS proteins in mice lacking the G  protein β-subunit Gβ5

Chen, Ching‐Kang; Eversole-Cire, Pamela; Zhang, Haikun; Mancino, Valeria; Chen, Yu-Jiun; He, Wei; Wensel, Theodore G.

doi:10.1073/pnas.0631825100

Cited by 192 publications

(227 citation statements)

References 38 publications

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“…The functional knock-out of all four R7 proteins, which takes place in the G␤5 knock-out mice, leads to multiple health problems, low body weight, and a high mortality rate (24). A less severe but also well identifiable phenotype was documented in the RGS9 knock-out mice.…”

Section: Novel Interacting Partner Of R7 Rgs Proteins 5135mentioning

confidence: 96%

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

Martemyanov

Yoo

Skiba

et al. 2005

Journal of Biological Chemistry

136

192

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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...

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Section: Novel Interacting Partner Of R7 Rgs Proteins 5135mentioning

confidence: 96%

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

Martemyanov

Yoo

Skiba

et al. 2005

Journal of Biological Chemistry

136

192

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“…Thus, for example, ablation of G␥ subunit expression destabilizes uncomplexed G␤ (31). Furthermore, RGS proteins containing the G protein ␥-like domain (RGS6, RGS7, RGS9, and RGS11) are G␤ 5 binding partners; they are destabilized and degraded in mice lacking G␤ 5 , and reciprocally, G␤ 5 protein is degraded in the absence of a suitable interacting subunit (32,33). To examine the stability of G␣ and G␥ subunits as a function of G␤ suppression, we performed quantitative RT-PCR and Western blotting.…”

Section: Expression Of G␥ Subunits Was Down-regulated In the Cells Lamentioning

confidence: 99%

Analysis of C5a-mediated chemotaxis by lentiviral delivery of small interfering RNA

Hwang

Fraser

Choi

et al. 2003

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

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Immune cells respond to chemotactic signals by means of G protein-coupled receptors. Attempts to elucidate the function of specific G protein family members in these responses is complicated by redundancy among the different G protein isoforms. We have used lentiviral-based RNA interference to eliminate expression of specific G protein subunits selectively in J774A.1 mouse macrophages. The chemotactic response to the complement factors C5a and C3a is ablated in cells lacking G␤2 but is unaffected in cells lacking G␤1, G␣i2, or G␣i3. Similarly, the C5a-mediated calcium response of single cells is either absent or significantly delayed and weakened by G␤2 knockdown. Assessment of Akt1 phosphorylation levels in response to C5a shows rapid and sustained phosphorylation in both wild-type cells and cells lacking G␤1. Cells lacking G␤2 retain the rapid response but cannot sustain phosphoAkt1 levels. The phenotype of cells lacking G␤2 can be reversed by overexpression of either human G␤2 or mouse G␤1. These data demonstrate the usefulness of lentiviral-based RNA interference in the systematic analysis of a signaling pathway, and they suggest that in J774A.1 cells, G␤2-derived G␤␥ is the most effective mediator of chemotaxis to C5a.

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“…These studies revealed that Gb5 and R7BP knockout mice have dramatically diminished levels of RGS9-2 protein (Chen et al, 2003;Anderson et al, 2009), that loss of R7BP affects RGS9-2 localization and striatal signaling (Anderson et al, 2009), and that pharmacological manipulations, or changes in neuronal excitability affect the composition of R7 complexes in the striatum (Anderson et al, 2009;Psifogeorgou et al, 2011). Recent evidence from genetic mouse models suggests that R7BP has a key role in regulation of GPCR responses in the basal ganglia, via interactions with RGS9-2 and RGS7.…”

Section: Introductionmentioning

confidence: 99%

“…Members of the R7 family share several domains and form constitutive complexes with the type 5 G protein b subunit (Gb5) (Sondek and Siderovski, 2001;Cheever et al, 2008). The R7-Gb5 association is essential for the protein's stability and function (He et al, 2000;Chen et al, 2003). R7 proteins also share a DEP domain (Martemyanov et al, 2003;Ballon et al, 2006), which is required for their interaction with the adaptor molecules R9AP in the retina (Hu and Wensel, 2002) and R7 family binding protein (R7BP) in the brain (Martemyanov et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

R7BP Modulates Opiate Analgesia and Tolerance but not Withdrawal

Terzi

Cao

Agrimaki

et al. 2011

Neuropsychopharmacol

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The adaptor protein R7 family binding protein (R7BP) modulates G protein coupled receptor (GPCR) signaling and desensitization by controlling the function of regulator of G protein signaling (RGS) proteins. R7BP is expressed throughout the brain and appears to modulate the membrane localization and stability of three proteins that belong to R7 RGS family: RGS6, RGS7, and RGS9-2. RGS9-2 is a potent negative modulator of opiate and psychostimulant addiction and promotes the development of analgesic tolerance to morphine, whereas the role of RGS6 and RGS7 in addiction remains unknown. Recent studies revealed that functional deletion of R7BP reduces R7 protein activity by preventing their anchoring to the cell membrane and enhances GPCR responsiveness in the basal ganglia. Here, we take advantage of R7BP knockout mice in order to examine the way interventions in R7 proteins function throughout the brain affect opiate actions. Our results suggest that R7BP is a negative modulator of the analgesic and locomotor activating actions of morphine. We also report that R7BP contributes to the development of morphine tolerance. Finally, our data suggest that although prevention of R7BP actions enhances the analgesic responses to morphine, it does not affect the severity of somatic withdrawal signs. Our data suggest that interventions in R7BP actions enhance the analgesic effect of morphine and prevent tolerance, without affecting withdrawal, pointing to R7BP complexes as potential new targets for analgesic drugs.

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Instability of GGL domain-containing RGS proteins in mice lacking the G protein β-subunit Gβ5

Cited by 192 publications

References 38 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

Analysis of C5a-mediated chemotaxis by lentiviral delivery of small interfering RNA

R7BP Modulates Opiate Analgesia and Tolerance but not Withdrawal

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