Evolution of the Regulators of G-Protein Signaling Multigene Family in Mouse and Human

Sierra, David A.; Gilbert, Debra J.; Householder, Deborah B.; Grishin, Nick V.; Yu, Kan; Ukidwe, Pallavi; Barker, Sheryll A.; He, Wei; Wensel, Theodore G.; Otero, Glen; Brown, Greg; Copeland, Neal G.; Jenkins, Nancy A.; Wilkie, Thomas M.

doi:10.1006/geno.2002.6693

Cited by 87 publications

(58 citation statements)

References 53 publications

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“…The nematode C. elegans possesses 12 RGS proteins (Sierra et al., 2002). According to the results of Basic Local Alignment Search Tool (BLAST), two members of the family, rgs‐1 and rgs‐2 , are closely related to the mammalian RGS14 (Figure 6a).…”

Section: Resultsmentioning

confidence: 99%

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

et al. 2018

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SummaryDisruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild‐type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS‐14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging.

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Section: Resultsmentioning

confidence: 99%

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

et al. 2018

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“…Furthermore, it is noteworthy that the human and mouse RGS-Rz genes are closely linked to the opioid receptor genes. The RGSZ1, GAIP, and RGSZ2 genes are found close to the k (opioid-like receptor 1), ORL1, and m-opioid receptor genes, respectively, suggesting that these pairs of genes can be coordinately expressed (Sierra et al, 2002). In fact, the GAIP and ORL1 genes lie head to head and share promoter elements (Ito et al, 2000), indicating that the physical linkage between these GPCRs and RGS-Rz proteins may play a significant role in the regulation of their signaling.…”

Section: Introductionmentioning

confidence: 99%

“…The RGSZ2 described by Jordan et al (1999) lacks the amphipathic helix at the N terminus and the C-terminal PDZ-binding motif present in GAIP, exhibiting closer homology to RGSZ1. The RGS-Rz genes are the most highly conserved RGS subfamily in metazoans, and one, two, or three copies of these RGS-Rz genes existing in flies, worms, and mammals, respectively (Sierra et al, 2002). Furthermore, it is noteworthy that the human and mouse RGS-Rz genes are closely linked to the opioid receptor genes.…”

Section: Introductionmentioning

confidence: 99%

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

Garzón

Rodríguez-Muñoz

López-Fando

et al. 2005

Neuropsychopharmacol

104

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The regulator of G-protein signaling RGS17(Z2) is a member of the RGS-Rz subfamily of GTPase-activating proteins (GAP) that efficiently deactivate GazGTP subunits. We have found that in the central nervous system (CNS), the levels of RGSZ2 mRNA and protein are elevated in the hypothalamus, midbrain, and pons-medulla, and that RGSZ2 is glycosylated in synaptosomal membranes isolated from CNS tissue. In analyzing the function of RGSZ2 in the CNS, we found that when the expression of RGSZ2 was impaired, the antinociceptive response to morphine and [D-Ala 2 , N-MePhe 4 , Gly-ol 5 ]-enkephalin (DAMGO) augmented. This potentiation involved m-opioid receptors and increased tolerance to further doses of these agonists administered 24 h later. High doses of morphine promoted agonist desensitization even within the analgesia time-course, a phenomenon that appears to be related to the great capacity of morphine to activate Gz proteins. In contrast, the knockdown of RGSZ2 proteins did not affect the activity of d receptor agonists, [D-Pen 2,5 ]-enkephalin (DPDPE), and [D-Ala 2 ] deltorphin II. In membranes from periaqueductal gray matter (PAG), both RGSZ2 and the related RGS20(Z1) co-precipitated with m-opioid receptors. While a morphine challenge reduced the association of Gi/o/z with m receptors, it increased their association with the RGSZ2 and RGSZ1 proteins. However, only Gaz subunits co-precipitated with RGSZ2. Doses of morphine that produced acute tolerance maintained the association of Ga subunits with RGSZ proteins even after the analgesic effects had ceased. These results indicate that both RGSZ1 and RGSZ2 proteins influence m receptor signaling by sequestering Ga subunits, therefore behaving as effector antagonists.

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“…RGS6 is a member of the RGS 1 protein family of which 20 or more genes exist in humans (1). From initial genetic studies in yeast implicating the RGS protein Sst2p in negative regulation of pheromone signaling, much evidence suggests RGS proteins may act to facilitate termination of heterotrimeric G protein signaling initiated by stimulation of G protein-coupled receptors (2,3).…”

mentioning

confidence: 99%

Mild Heat and Proteotoxic Stress Promote Unique Subcellular Trafficking and Nucleolar Accumulation of RGS6 and Other RGS Proteins

Chatterjee

Fisher

2003

Journal of Biological Chemistry

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RGS6 is a member of the RGS 1 protein family of which 20 or more genes exist in humans (1). From initial genetic studies in yeast implicating the RGS protein Sst2p in negative regulation of pheromone signaling, much evidence suggests RGS proteins may act to facilitate termination of heterotrimeric G protein signaling initiated by stimulation of G protein-coupled receptors (2, 3). Indeed, the hallmark RGS domain, present in all RGS proteins, mediates their interaction with and enhancement of the intrinsic GTPase activity of heterotrimeric G protein ␣-subunits in vitro. Because G␣ subunits are active when bound to GTP, and form inactive complexes with cognate G␤␥ subunits following GTP hydrolysis, such actions of RGS proteins would shut down signaling by both active G␣ and G␤␥ signaling proteins. This activity would explain the enhancement of G protein signaling observed in genetic mutants lacking RGS proteins in Saccharomyces cerevisiae and Caenorhabditis elegans (4, 5). However, less is known about the signaling and physiological role of these proteins in mammals, although genetic knockout of RGS9 in mice showed that RGS9 is essential for acceleration of GTP hydrolysis by transducin (Gt) and normal recovery of the photoresponse (6).Yet, there are many unanswered questions regarding the structure and function of RGS proteins. Although some RGS proteins exhibit specificity toward specific G␣ subunits, the number of RGS proteins that exist far exceeds that of their presumed G protein targets. RGS proteins are predicted to accumulate at the plasma membrane to function as GAPs for G proteins, yet this evidence is lacking for all but a few RGS proteins. Indeed, we demonstrated localization of RGS proteins in the cytoplasm, nucleus, and Golgi and provided evidence for extra-RGS domain sequences in subcellular targeting of these proteins (7), and several other laboratories have reported localization of RGS proteins in the nucleus (8 -11). Also, considerable structural differences exist among members of the RGS family and distinct subfamilies of these proteins have been described (2, 3). These subfamilies share similarities both

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Evolution of the Regulators of G-Protein Signaling Multigene Family in Mouse and Human

Cited by 87 publications

References 53 publications

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

Mild Heat and Proteotoxic Stress Promote Unique Subcellular Trafficking and Nucleolar Accumulation of RGS6 and Other RGS Proteins

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