G protein signaling–biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists

The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity, and biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor, which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein–biased mu opioid receptor (MOR) agonists SR-17018 and SR-14968 stabilize the MOR in a wash-resistant yet antagonist-reversible G protein–signaling state. Furthermore, we demonstrate that these structurally related biased agonists are noncompetitive for radiolabeled MOR antagonist binding, and while they stimulate G protein signaling in mouse brains, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR-17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long-lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.

Increased Expression Regulator of G-protein Signaling 1 Predicts Unfavorable Prognosis of Gastric Cancer

Background: Regulator of G-protein signaling 1 (RGS1) expression has been reported to be a prognostic marker for specific cancers, but its function in gastric cancer (GC) remains to be elucidated. Methods: RNA-sequencing data and clinicopathologic characteristics of 434 GC patients were collected from The Cancer Genome Atlas (TCGA) database. the expression level of RGS1 in GC tissues are significantly higher than pan-cancer tissues. The high expression of RGS1 is associated with worse progression of GC. The diagnostic value of RGS1 was evaluated by calculating receiver operating characteristic curve (ROC). Cox proportional hazards regression modeling and Kaplan-Meier curves were used to explore clinicopathologic characteristics related to overall survival (OS) in GC patients. Immunohistochemistry (IHC) was used to evaluate the impact of RGS1 on prognosis in the study population in our center. Results: The expression level of RGS1 in GC were significantly higher comparing with normal stomach tissues (p=0.016). The expression of RGS1 was significantly associated with poor differentiation (p=1.917e-06), T stage (p=1042e-04), N stage (p=0.049) and TNM stage (p=0.004). The area under the ROC curve was 0.610. High RGS1 expression was significantly associated with poor OS (p=0.002). Multivariate analysis shows high RGS1 expression(p=0.031) was independent poor prognostic factors of OS. Conclusion: High RGS1 protein expression was correlated with poor clinical outcomes, which was also independent predictors of worse OS. RGS1 may be a promising target for a new GC therapy.

Oxytocin Is a Positive Allosteric Modulator of κ-Opioid Receptors but Not δ-Opioid Receptors in the G Protein Signaling Pathway

Oxytocin (OT) influences various physiological functions such as uterine contractions, maternal/social behavior, and analgesia. Opioid signaling pathways are involved in one of the analgesic mechanisms of OT. We previously showed that OT acts as a positive allosteric modulator (PAM) and enhances μ-opioid receptor (MOR) activity. In this study, which focused on other opioid receptor (OR) subtypes, we investigated whether OT influences opioid signaling pathways as a PAM for δ-OR (DOR) or κ-OR (KOR) using human embryonic kidney-293 cells expressing human DOR or KOR, respectively. The CellKeyTM results showed that OT enhanced impedance induced by endogenous/exogenous KOR agonists on KOR-expressing cells. OT did not affect DOR activity induced by endogenous/exogenous DOR agonists. OT potentiated the KOR agonist-induced Gi/o protein-mediated decrease in intracellular cAMP, but did not affect the increase in KOR internalization caused by the KOR agonists dynorphin A and (-)-U-50488 hydrochloride (U50488). OT did not bind to KOR orthosteric binding sites and did not affect the binding affinities of dynorphin A and U50488 for KOR. These results suggest that OT is a PAM of KOR and MOR and enhances G protein signaling without affecting β-arrestin signaling. Thus, OT has potential as a specific signaling-biased PAM of KOR.

The G protein database, GproteinDb

Two-thirds of signaling substances, several sensory stimuli and over one-third of drugs act via receptors coupling to G proteins. Here, we present an online platform for G protein research with reference data and tools for analysis, visualization and design of scientific studies across disciplines and areas. This platform may help translate new pharmacological, structural and genomic data into insights on G protein signaling vital for human physiology and medicine. The G protein database is accessible at https://gproteindb.org.