Disease relevance of RGS7

• Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling [1].
• The subcellular localization of Gbeta(5) and RGS7 was examined in rat PC12 pheochromocytoma cells and mouse brain [2].
• In situ hybridization revealed a transient, robust early increase in RGS7 mRNA levels in the dentate gyrus after ischemia [3].

High impact information on RGS7

• Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function [1].
• Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function [1].
• Palmitoylation regulates plasma membrane-nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family [4].
• Here, we identify R7BP, a novel neuronally expressed protein that binds R7-Gbeta5 complexes and shuttles them between the plasma membrane and nucleus [4].
• Here we confirm through targeted mutagenesis of RGS7 that these ET-identified residues are critical for RGS domain regulation and are likely to function as global determinants of RGS function [5].

Biological context of RGS7

• The inhibitory interaction between 14-3-3 and RGS7 requires phosphorylation of serine 434 of RGS7 [6].
• RGS7 attenuates signal transduction through the G(alpha q) family of heterotrimeric G proteins in mammalian cells [7].
• To gain insight into its function, we used yeast two-hybrid analysis to screen a human whole brain cDNA library in order to identify proteins that interact specifically with the N-terminus of human RGS7 (amino acid residues 1-248) [8].
• Our results suggest that RGS7 could play a role in synaptic vesicle exocytosis through its interaction with snapin [8].
• We observed that RGS4 mRNA and protein were concomitantly augmented with increased cell density and decreased by exposure of PC12M cells to nerve growth factor, whereas RGS7 was unaffected [9].

Anatomical context of RGS7

• After expression in Sf9 cells, complexes of both RGS6 and RGS7 with the Gbeta5 subunit (but not Gbetas 1-4) are found in the cytosol [10].
• Palmitoylation and plasma membrane targeting of RGS7 are promoted by alpha o [11].
• Both nuclear and cytosolic localization of Gbeta(5) and RGS7 was evident in PC12 cells by immunocytochemical staining [2].
• Endogenous levels of RGS7 exceeded RGS4 by 30-40-fold, and studies of cultured cells revealed regulatory differences between the two proteins [9].
• Ischemia-induced increase in RGS7 mRNA expression in gerbil hippocampus [3].

Associations of RGS7 with chemical compounds

• RGS7-deficient mice showed an increased response to both [D-Ala(2)]deltorphin II and DPDPE analgesic effects [12].
• Cellular stimulation by TNF-alpha transiently decreased the phosphorylation of serine 434 of RGS7, abrogating the inhibitory interaction with 14-3-3 [6].
• Binding of 14-3-3 is mediated by a conserved phosphoserine located in the Galpha-interacting portion of the RGS domain; interaction with 14-3-3 inhibits the GAP activity of RGS7, depends upon phosphorylation of a conserved residue within the RGS domain, and results in inhibition of GAP function [13].
• To examine potential palmitoylation sites of RGS7, several cysteines were substituted with serines. beta(5)RGS7C133S failed to localize to plasma membranes when coexpressed with alpha(o), suggesting cysteine 133 of RGS7 as a putative palmitoylation site [11].
• Coexpression of the proteins RGS3 and RGS7 together with CFTR and alphaG(i2) partially recovered activation by IBMX/forskolin [14].

Other interactions of RGS7

• A single intracerebroventricular (i.c.v.) ED(80) analgesic dose of morphine gave rise to acute tolerance in control mice, but did not promote tolerance in RGS6, RGS7, RGS9-2, or RGS11 knockdown animals [12].
• RGS7 and RGS17 had overlapping distribution profiles and were both noticeably enriched in the cerebellum [15].
• The degradation of RGS7 is inhibited by interaction with a C-terminal domain of polycystin, the protein encoded by PKD1, a gene involved in autosomal-dominant polycystic kidney disease [16].
• RGS4 N terminus fused to either full-length or the C terminus of RGS7 successfully complemented sst2Delta [17].
• Here we show that 14-3-3 proteins associate with RGS7 and RGS3 [13].

Analytical, diagnostic and therapeutic context of RGS7

• The reconstituted Gbeta5-RGS dimers are similar to the native retinal complex in their behavior on gel-filtration and cation-exchange chromatographies and can be immunoprecipitated with either anti-Gbeta5 or anti-RGS7 antibodies [18].

References