The regulators of the G protein signaling (RGS) proteins are responsible for the rapid acceleration of the GTPase-activity intrinsic to the heterotrimeric G protein alpha subunits. As GTPase-activating proteins (GAP), the RGS proteins negatively regulate the G-protein signals. Recently, the RGS proteins are known to be one of the important regulators of opioid signal transduction and the development of tolerance. The aim of this study was to review the recent discovery and understanding of the role of RGS proteins in opioid signaling and the development of tolerance. This information will be useful for medical personnel, particularly those involved in anesthesia and pain medicine, by helping them improve the effective use of opioids and develop new drugs that can prevent opioid tolerance.
Acceleration ; Analgesics, Opioid ; Anesthesia ; GTP-Binding Protein alpha Subunits ; GTP-Binding Proteins ; GTPase-Activating Proteins ; RGS Proteins* ; Signal Transduction

Regulators of G-protein signaling (RGS) proteins are regulators of Ca2+ signaling that accelerate the GTPase activity of the G-protein alpha-subunit. RGS1, RGS2, RGS4, and RGS16 are expressed in the pancreas, and RGS2 regulates G-protein coupled receptor (GPCR)-induced Ca2+ oscillations. However, the role of RGS4 in Ca2+ signaling in pancreatic acinar cells is unknown. In this study, we investigated the mechanism of GPCR-induced Ca2+ signaling in pancreatic acinar cells derived from RGS4-/- mice. RGS4-/- acinar cells showed an enhanced stimulus intensity response to a muscarinic receptor agonist in pancreatic acinar cells. Moreover, deletion of RGS4 increased the frequency of Ca2+ oscillations. RGS4-/- cells also showed increased expression of sarco/endoplasmic reticulum Ca2+ ATPase type 2. However, there were no significant alterations, such as Ca2+ signaling in treated high dose of agonist and its related amylase secretion activity, in acinar cells from RGS4-/- mice. These results indicate that RGS4 protein regulates Ca2+ signaling in mouse pancreatic acinar cells.
Acinar Cells ; Amylases ; Animals ; Calcium-Transporting ATPases ; GTP Phosphohydrolases ; GTP-Binding Proteins ; Mice ; Pancreas ; Proteins ; Receptors, Muscarinic ; Reticulum ; RGS Proteins

OBJECTIVETo investigate the new genetic variations of regulator of G-protein signalling 2 (RGS2) gene in Kazakh hypertensives.

METHODSTotally 94 Kazakh patients with essential hypertension were enrolled and genomic DNA was extracted from their peripheral blood leukocytes. All the exon regions and their flanking sequences of RGS2 were directly sequenced.

RESULTSWe identified 13 variants including 5 common- single nucleotide polymorphisms with a minor allele frequency over 5%single nucleotide polymorphisms and 8 novel variations in 94 Kazakh hypertensives. Among these variations, 2 were in the introns and 7 in the promoter region. One subject had a G-to-C substitution at nucleotide 54 in exon 1, which lead to an amino acid substitution from K-to-N at position 18; another individual had an A-to-G substitution at nucleotide 2422 in exon 5, resulting in an amino acid from Y-to-C at position 178. Among eight common single nucleotide polymorphisms, -638A>G, -395G>C, 1891-1892TC I/D, and 2971G>C,and -43A>T and 2297A>G were in tight linkage disequilibrium with an r-square of more than 0.8, respectively.

CONCLUSIONSThe variants and their frequencies in RGS2 gene in Kazakh hypertensives may have ethnic differences when compared with other populations. The frequencies of the mutations are low in this population, and whether they influence blood pressure regulation requires further functional experiments.

Adult ; China ; Female ; Genetic Variation ; Humans ; Hypertension ; genetics ; Linkage Disequilibrium ; Male ; Middle Aged ; Minority Groups ; RGS Proteins ; genetics

OBJECTIVETo investigate the association of the 1891-1892del TC polymorphism of regulator of G-protein signalling 2 (RGS2) gene with hypertension in Xinjiang Kazakh population.

METHODSThe case-control study was performed in 444 cases and 489 controls. The genotypes of the individuals in the 1891-1892del TC locus were identified by TaqMan method.

RESULTSA significant association was observed between the1891-1892TC insertion/deletion polymorphism with hypertension in men (OR=1.698, P=0.03) and in the total population (OR=1.32, P=0.044). The mean systolic blood pressure and serum uric acid levels of the ID+DD carriers were significantly higher than that of the II carriers (adjusted, P=0.04 and P<0.01).

CONCLUSIONThe results suggest that the D allele of the 1891-1892TC insertion/deletion locus of the RGS2 gene might be an independent risk factor for hypertension in Xinjiang Kazakhs; and the polymorphism may have some influence on serum uric acid level in this population.

Adult ; Aged ; Asian Continental Ancestry Group ; ethnology ; genetics ; Blood Pressure ; Case-Control Studies ; China ; Female ; Genetic Predisposition to Disease ; Humans ; Hypertension ; blood ; ethnology ; genetics ; physiopathology ; Male ; Middle Aged ; Polymorphism, Genetic ; RGS Proteins ; genetics ; Risk Factors ; Uric Acid ; blood

Tumor-associated macrophages (TAMs) play crucial roles in tumor progression and immune responses. However, mechanisms of driving TAMs to antitumor function remain unknown. Here, transcriptome profiling analysis of human oral cancer tissues indicated that regulator of G protein signaling 12 (RGS12) regulates pathologic processes and immune-related pathways. Mice with RGS12 knockout in macrophages displayed decreased M1 TAMs in oral cancer tissues, and extensive proliferation and invasion of oral cancer cells. RGS12 increased the M1 macrophages with features of increased ciliated cell number and cilia length. Mechanistically, RGS12 associates with and activates MYC binding protein 2 (MYCBP2) to degrade the cilia protein kinesin family member 2A (KIF2A) in TAMs. Our results demonstrate that RGS12 is an essential oral cancer biomarker and regulator for immunosuppressive TAMs activation.
Mice ; Humans ; Animals ; Tumor-Associated Macrophages/metabolism* ; Carcinoma, Squamous Cell ; Squamous Cell Carcinoma of Head and Neck ; Mouth Neoplasms ; GTP-Binding Proteins/metabolism* ; Head and Neck Neoplasms ; Ubiquitin-Protein Ligases/metabolism* ; Adaptor Proteins, Signal Transducing/metabolism* ; RGS Proteins/metabolism* ; Kinesins/metabolism* ; Repressor Proteins/metabolism*