Class Of G-protein Coupled Receptors Research Articles

Structural Insights into Partial Activation of the Prototypic G Protein-Coupled Adenosine A2A Receptor.

The adenosine A2A receptor (A2AAR) belongs to the rhodopsin-like G protein-coupled receptor (GPCR) family, which constitutes the largest class of GPCRs. Partial agonists show reduced efficacy as compared to physiological agonists and can even act as antagonists in the presence of a full agonist. Here, we determined an X-ray crystal structure of the partial A2AAR agonist 2-amino-6-[(1H-imidazol-2-ylmethyl)sulfanyl]-4-p-hydroxyphenyl-3,5-pyridinedicarbonitrile (LUF5834) in complex with the A2AAR construct A2A-PSB2-bRIL, stabilized in its inactive conformation and being devoid of any mutations in the ligand binding pocket. The determined high-resolution structure (2.43 Å) resolved water networks and crucial binding pocket interactions. A direct hydrogen bond of the p-hydroxy group of LUF5834 with T883.36 was observed, an amino acid that was mutated to alanine in the most frequently used A2AAR crystallization constructs thus preventing the discovery of its interactions in most of the previous A2AAR co-crystal structures. G protein dissociation studies confirmed partial agonistic activity of LUF5834 as compared to that of the full agonist N-ethylcarboxamidoadenosine (NECA). In contrast to NECA, the partial agonist was still able to bind to the receptor construct locked in its inactive conformation by an S913.39K mutation, although with an affinity lower than that at the native receptor. This could explain the compound's partial agonistic activity: while full A2AAR agonists bind exclusively to the active conformation, likely following conformational selection, partial agonists bind to active as well as inactive conformations, showing higher affinity for the active conformation. This might be a general mechanism of partial agonism also applicable to other GPCRs.

The nematode-trapping fungus Arthrobotrys oligospora detects prey pheromones via G protein-coupled receptors.

The ability to sense prey-derived cues is essential for predatory lifestyles. Under low-nutrient conditions, Arthrobotrys oligospora and other nematode-trapping fungi develop dedicated structures for nematode capture when exposed to nematode-derived cues, including a conserved family of pheromones, the ascarosides. A. oligospora senses ascarosides via conserved MAPK and cAMP-PKA pathways; however, the upstream receptors remain unknown. Here, using genomic, transcriptomic and functional analyses, we identified two families of G protein-coupled receptors (GPCRs) involved in sensing distinct nematode-derived cues. GPCRs homologous to yeast glucose receptors are required for ascaroside sensing, whereas Pth11-like GPCRs contribute to ascaroside-independent nematode sensing. Both GPCR classes activate conserved cAMP-PKA signalling to trigger trap development. This work demonstrates that predatory fungi use multiple GPCRs to sense several distinct nematode-derived cues for prey recognition and to enable a switch to a predatory lifestyle. Identification of these receptors reveals the molecular mechanisms of cross-kingdom communication via conserved pheromones also sensed by plants and animals.

Mapping the interaction site for β-arrestin-2 in the prokineticin 2 receptor

G protein-coupled receptors (GPCRs) are a family of cell membrane receptors that couple and activate heterotrimeric G proteins and their associated intracellular signalling processes after ligand binding. Although the carboxyl terminal of the receptors is essential for this action, it can also serve as a docking site for regulatory proteins such as the β-arrestins. Prokineticin receptors (PKR1 and PKR2) are a new class of GPCRs that are able to activate different classes of G proteins and form complexes with β-arrestins after activation by the endogenous agonists PK2. The aim of this work was to define the molecular determinants within PKR2 that are required for β-arrestin-2 binding and to investigate the role of β-arrestin-2 in the signalling pathways induced by PKR2 activation. Our data show that PKR2 binds constitutively to β-arrestin-2 and that this process occurs through the core region of the receptor without being affected by the carboxy-terminal region. Indeed, a PKR2 mutant lacking the carboxy-terminal amino acids retains the ability to bind constitutively to β-arrestin-2, whereas a mutant lacking the third intracellular loop does not. Overall, our data suggest that the C-terminus of PKR2 is critical for the stability of the β-arrestin-2-receptor complex in the presence of PK2 ligand. This leads to the β-arrestin-2 conformational change required to initiate intracellular signalling that ultimately leads to ERK phosphorylation and activation.

Lipid regulation of the glucagon receptor family.

The glucagon receptor family are typical class B1 G protein-coupled receptors (GPCRs) with important roles in metabolism, including the control of pancreas, brain, and liver function. As proteins with seven transmembrane domains, GPCRs are intimately in contact with lipid bilayers and therefore can be putatively regulated by interactions with their lipidic components, including cholesterol, sphingolipids, and other lipid species. Additionally, these receptors, as well as the agonists they bind to, can undergo lipid modifications, which can influence their binding capacity and/or elicit modified or biased signalling profiles. While the effect of lipids, and in particular cholesterol, has been widely studied for other GPCR classes, information about their role in regulating the glucagon receptor family is only beginning to emerge. Here we summarise our current knowledge on the effects of cholesterol modulation of glucagon receptor family signalling and trafficking profiles, as well as existing evidence for specific lipid-receptor binding and indirect effects of lipids via lipid modification of cognate agonists. Finally, we discuss the different methodologies that can be employed to study lipid-receptor interactions and summarise the importance of this area of investigation to increase our understanding of the biology of this family of metabolically relevant receptors.

Orphan GPCR GPRC5C Facilitates Angiotensin II-Induced Smooth Muscle Contraction.

GPCRs (G-protein-coupled receptors) play a central role in the regulation of smooth muscle cell (SMC) contractility, but the function of SMC-expressed orphan GPCR class C group 5 member C (GPRC5C) is unclear. The aim of this project is to define the role of GPRC5C in SMC in vitro and in vivo. We studied the role of GPRC5C in the regulation of SMC contractility and differentiation in human and murine SMC in vitro, as well as in tamoxifen-inducible, SMC-specific GPRC5C knockout mice under basal conditions and in vascular disease in vivo. Mesenteric arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed ex vivo significantly reduced angiotensin II (Ang II)-dependent calcium mobilization and contraction, whereas responses to other relaxant or contractile factors were normal. In vitro, the knockdown of GPRC5C in human aortic SMC resulted in diminished Ang II-dependent inositol phosphate production and lower myosin light chain phosphorylation. In line with this, tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed reduced Ang II-induced arterial hypertension, and acute inactivation of GPRC5C was able to ameliorate established arterial hypertension. Mechanistically, we show that GPRC5C and the Ang II receptor AT1 dimerize, and knockdown of GPRC5C resulted in reduced binding of Ang II to AT1 receptors in HEK293 cells, human and murine SMC, and arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice. Our data show that GPRC5C regulates Ang II-dependent vascular contraction by facilitating AT1 receptor-ligand binding and signaling.

Cryo-EM advances in GPCR structure determination.

G-protein-coupled receptors (GPCRs) constitute a prominent superfamily in humans, and are categorized into six classes (A through F) that play indispensable roles in cellular communication and therapeutics. Nonetheless, their structural comprehension has been limited by challenges in high-resolution data acquisition. This review highlights the transformative impact of cryogenic electron microscopy (cryo-EM) in the structural determinations of GPCR-G-protein complexes. Specific technologies such as nanobodies and mini-G-proteins stabilize complexes and facilitate structural determination. We discuss the structural alterations upon receptor activation in different GPCR classes, revealing their diverse mechanisms. These cryo-EM structures provide a robust foundation for comprehending GPCR function and pave the way for future breakthroughs in drug discovery and therapeutic targeting.

Transcriptome wide identification of neuropeptides and G protein-coupled receptors (GPCRs) in Sunn pest, Eurygaster integriceps Puton

Sunn pest (Eurygaster integriceps Puton) is major wheat pest causing economic damage. Neuropeptides and their receptors, G protein-coupled receptors (GPCRs), are involved in the regulation of insect physiology and behavior. Herein, a transcriptome-wide analysis was conducted in order to identify genes encoding neuropeptides, and putative GPCRs to gain insight into neuropeptide-modulated processes. De novo transcriptome assembly was undertaken using paired-end sequence reads derived from RNA samples collected from whole adults and yielded 582,398 contigs. In total, 46 neuropeptides have been identified, encompassing various known insect neuropeptide families. In addition, we discovered four previously uncharacterized neuroparsin peptides, which contributes to our understanding of the neuropeptide landscape. Furthermore, 85 putative neuropeptide GPCRs were identified, comprising three classes of GPCRs, A, B, C, and LGR, of which class C is not widely reported in insects. In addition, the identified GPCRs exhibited a remarkable 80% homology with the GPCRs found in the brown marmorated stink bug. It is noteworthy that these GPCRs displayed only a 20% homology to GPCRs from many other insect species. This information may be used to understand the neuropeptide-modulated physiology and behavior of Eurygaster integriceps, and to develop specific neuropeptide-based pest management strategies.

Novel substituted 4-(Arylethynyl)-Pyrrolo[2,3-d]pyrimidines negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) Treat depressive disorder in mice

In view of the fact that the G-protein-coupled receptors (GPCRs) sit at the top of the signaling pathways triggering a diverse range of signaling cascades towards a cellular event, GPCRs are regarded as central drug targets. mGlu5, a type of classical GPCRs, is highly expressed in the central nervous system (CNS) and responds to the neurotransmitter glutamate. Researches show that mGlu5 is a potential drug target for the treatment of depression. Up to now, multiple mGlu5 negative allosteric modulators (NAMs) have entered clinical trials, but no small molecule mGlu5 NAM has yet to reach market. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel mGlu5 NAMs. Among them, the novel compound 10b is a high-affinity mGluR5 antagonist, with an IC50 value of 11.5 nM. Besides, we evaluated the anti-depressant effect of compound 10b using the chronic unpredictable mild stress (CUMS)-induced depression model. The data showed that the mice in CUMS group were featured by decreased level of serum 5-HT and increased level of serum CORT, and the expression of synaptic proteins were reduced, including GluA1, GluA2, p-PKA, BDNF and TrkB. However, those factors for identifying sensitivity to depression-like behaviors could be improved by compound 10b treatment. The preliminary toxicology evaluations indicated that compound 10b had a good safety profile in vivo. Collectively, the compound 10b represents a promising lead compound for the treatment of depressive disorder.

Characterization of the real-time internalization of nine GPCRs reveals distinct dependence on arrestins and G proteins

G protein-coupled receptors (GPCRs) are seven transmembrane receptors that respond to external stimuli and undergo conformational changes to activate G proteins and modulate cellular processes leading to biological outcomes. To prevent overstimulation and prolonged exposure to stimuli, GPCRs are regulated by internalization. While the canonical GPCR internalization mechanism in mammalian cells is arrestin-dependent, clathrin-mediated endocytosis, more diverse GPCR internalization mechanisms have been described over the years. However, there is a lack of consistent methods used in the literature making it complicated to determine a receptor's internalization pathway. Here, we utilized a highly efficient time-resolved Förster resonance energy transfer (TR-FRET) internalization assay to determine the internalization profile of nine distinct GPCRs representing the GPCR classes A, B and C and with different G protein coupling profiles. This technique, coupled with clustered regularly interspaced palindromic repeats (CRISPR) engineered knockout cells allows us to effectively study the involvement of heterotrimeric G proteins and non-visual arrestins. We found that all the nine receptors internalized upon agonist stimulation in a concentration-dependent manner and six receptors showed basal internalization. Yet, there is no correlation between the receptor class and primary G protein coupling to the arrestin and G protein dependence for GPCR internalization. Overall, this study presents a platform for studying internalization that is applicable to most GPCRs and may even be extended to other membrane proteins. This method can be easily applicable to other endocytic machinery of interest and ultimately will lend itself towards the construction of comprehensive receptor internalization profiles.

Helix encoder: a compound-protein interaction prediction model specifically designed for class A GPCRs.

Class A G protein-coupled receptors (GPCRs) represent the largest class of GPCRs. They are essential targets of drug discovery and thus various computational approaches have been applied to predict their ligands. However, there are a large number of orphan receptors in class A GPCRs and it is difficult to use a general protein-specific supervised prediction scheme. Therefore, the compound-protein interaction (CPI) prediction approach has been considered one of the most suitable for class A GPCRs. However, the accuracy of CPI prediction is still insufficient. The current CPI prediction model generally employs the whole protein sequence as the input because it is difficult to identify the important regions in general proteins. In contrast, it is well-known that only a few transmembrane helices of class A GPCRs play a critical role in ligand binding. Therefore, using such domain knowledge, the CPI prediction performance could be improved by developing an encoding method that is specifically designed for this family. In this study, we developed a protein sequence encoder called the Helix encoder, which takes only a protein sequence of transmembrane regions of class A GPCRs as input. The performance evaluation showed that the proposed model achieved a higher prediction accuracy compared to a prediction model using the entire protein sequence. Additionally, our analysis indicated that several extracellular loops are also important for the prediction as mentioned in several biological researches.

Activity Map and Transition Pathways of G Protein-Coupled Receptor Revealed by Machine Learning.

Approximately, one-third of all U.S. Food and Drug Administration approved drugs target G protein-coupled receptors (GPCRs). However, more knowledge of protein structure-activity correlation is required to improve the efficacy of the drugs targeting GPCRs. In this study, we developed a machine learning model to predict the activation state and activity level of the receptors with high prediction accuracy. Furthermore, we applied this model to thousands of molecular dynamics trajectories to correlate residue-level conformational changes of a GPCR to its activity level. Finally, the most probable transition pathway between activation states of a receptor can be identified using the state-activity information. In addition, with this model, we can associate the contribution of each amino acid to the activation process. Using this method, we can design drugs that mainly target principal amino acids driving the transition between activation states of GPCRs. Our advanced method is generalizable to all GPCR classes and provides mechanistic insight into the activation mechanism in the receptors.

WNT stimulation induces dynamic conformational changes in the Frizzled-Dishevelled interaction.

Frizzleds (FZDs) are G protein-coupled receptors (GPCRs) that bind to WNT family ligands. FZDs signal through multiple effector proteins, including Dishevelled (DVL), which acts as a hub for several downstream signaling pathways. To understand how WNT binding to FZD stimulates intracellular signaling and influences downstream pathway selectivity, we investigated the dynamic changes in the FZD5-DVL2 interaction elicited by WNT-3A and WNT-5A. Ligand-induced changes in bioluminescence resonance energy transfer (BRET) between FZD5 and DVL2 or the isolated FZD-binding DEP domain of DVL2 revealed a composite response consisting of both DVL2 recruitment and conformational dynamics in the FZD5-DVL2 complex. The combination of different BRET paradigms enabled us to identify ligand-dependent conformational dynamics in the FZD5-DVL2 complex and distinguish them from ligand-induced recruitment of DVL2 or DEP to FZD5. The observed agonist-induced conformational changes at the receptor-transducer interface suggest that extracellular agonist and intracellular transducers cooperate through transmembrane allosteric interaction with FZDs in a ternary complex reminiscent of that of classical GPCRs.

Itch receptor MRGPRX4 interacts with the receptor activity–modifying proteins

Cholestatic itch is a severe and debilitating symptom in liver diseases with limited treatment options. The class AG protein-coupled receptor (GPCR) Mas-related GPCR subtype X4 (MRGPRX4) has been identified as a receptor for bile acids, which are potential cholestatic pruritogens. An increasing number of GPCRs have been shown to interact with receptor activity-modifying proteins (RAMPs), which can modulate different aspects of GPCR biology. Using a combination of multiplexed immunoassay and proximity ligation assay, we show that MRGPRX4 interacts with RAMPs. The interaction of MRGPRX4 with RAMP2, but not RAMP1 or 3, causes attenuation of basal and agonist-dependent signaling, which correlates with a decrease of MRGPRX4 cell surface expression as measured using a quantitative NanoBRET pulse-chase assay. Finally, we use AlphaFold Multimer to predict the structure of the MRGPRX4-RAMP2 complex. The discovery that RAMP2 regulates MRGPRX4 may have direct implications for future drug development for cholestatic itch.

Functional crosstalk between angiotensin receptors (types 1 and 2) and relaxin family peptide receptor 1 (RXFP1): Implications for the therapeutic targeting of fibrosis.

Class A, rhodopsin-like, G-protein-coupled receptors (GPCRs) are by far the largest class of GPCRs and are integral membrane proteins used by various cells to convert extracellular signals into intracellular responses. Initially, class A GPCRs were believed to function as monomers, but a growing body of evidence has emerged to suggest that these receptors can function as homodimers and heterodimers and can undergo functional crosstalk to influence the actions of agonists or antagonists acting at each receptor. This review will focus on the angiotensin type 1 (AT1 ) and type 2 (AT2 ) receptors, as well as the relaxin family peptide receptor 1 (RXFP1), each of which have their unique characteristics but have been demonstrated to undergo some level of interaction when appropriately co-expressed, which influences the function of each receptor. In particular, this receptor functional crosstalk will be discussed in the context of fibrosis, the tissue scarring that results from a failed wound-healing response to injury, and which is a hallmark of chronic disease and related organ dysfunction.

The Nature of Functional Features of Different Classes of G-Protein-Coupled Receptors.

G-protein-coupled receptors (GPCRs) are a critical family in the human proteome and are involved in various physiological processes. They are also the most important drug target, with approximately 30% of approved drugs acting on such receptors. The members of the family are divided into six classes based on their structural and functional characteristics. Understanding their structural-functional relationships will benefit us in future drug development. In this article, we investigate the features of protein function, structure, and energy that describe the dynamics of the GPCR activation process between different families. GPCRs straddle the cell membrane and transduce signals from outside the membrane into the cell. During the process, the conformational change in GPCRs that is activated by the binding of signal molecules is essential. During the binding process, different types of signal molecules result in different signal transfer efficiencies. Therefore, the GPCR classes show a variety of structures and activation processes. Based on the experimental crystal structures, we modeled the activation process of the β2 adrenergic receptor (β2AR), glucagon receptor (GCGR), and metabotropic glutamate receptor 2 (mGluR2), which represent class A, B, and C GPCRs, respectively. We calculated their activation free-energy landscapes and analyzed the structure-energy-function relationship. The results show a consistent picture of the activation mechanisms between different types of GPCRs. This could also provide us a way to understand other signal transduction proteins.

Pan-cancer functional analysis of somatic mutations in G protein-coupled receptors

G Protein-coupled receptors (GPCRs) are the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used a dataset of mutations found in patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 genomes project. We explored cancer-related mutation patterns in all GPCR classes combined and individually. While the location of the mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment in cancer patients was observed among class-specific conserved motifs in GPCRs such as the Class A “DRY” motif. A Two-Entropy Analysis confirmed the correlation between residue conservation and cancer-related mutation frequency. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). Our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, but also discovered novel GPCRs which had not been linked to cancer before such as the P2Y Receptor 10 (P2RY10). Overall, this study presents a list of GPCRs that are amenable to experimental follow up to elucidate their role in cancer.

Optimization of Discrete Wavelet Transform Feature Representation and Hierarchical Classification of G-Protein Coupled Receptor Using Firefly Algorithm and Particle Swarm Optimization

Ineffective protein feature representation poses problems in protein classification in hierarchical structures. Discrete wavelet transform (DWT) is a feature representation method which generates global and local features based on different wavelet families and decomposition levels. To represent protein sequences, the proper wavelet family and decomposition level must be selected. This paper proposed a hybrid optimization method using particle swarm optimization and the firefly algorithm (FAPSO) to choose the suitable wavelet family and decomposition level of wavelet transformation for protein feature representation. The suggested approach improved on the work of earlier researchers who, in most cases, manually selected the wavelet family and level of decomposition based solely on experience and not on data. The paper also applied the virtual class methods to overcome the error propagation problems in hierarchical classification. The effectiveness of the proposed method was tested on a G-Protein Coupled Receptor (GPCR) protein data set consisting of 5 classes at the family level, 38 classes at the subfamily level, and 87 classes at the sub-subfamily level. Based on the result obtained, the most selected wavelet family and decomposition level chosen to represent GPCR classes by FAPSO are Biorthogonal wavelets and decomposition level 1, respectively. The experimental results show that the representation of GPCR protein using the FAPSO algorithm with virtual classes can yield 97.9%, 86.9%, and 81.3% classification accuracy at the family, subfamily, and sub-subfamily levels, respectively. In conclusion, the result shows that the selection of optimized wavelet family and decomposition level by the FAPSO algorithm, and the virtual class method can be potentially used as the feature representation method and a hierarchical classification method for GPCR protein.

Review: The evolution of peptidergic signaling in Cnidaria and Placozoa, including a comparison with Bilateria.

Bilateria have bilateral symmetry and are subdivided into Deuterostomia (animals like vertebrates) and Protostomia (animals like insects and mollusks). Neuropeptides occur in both Proto- and Deuterostomia and they are frequently structurally related across these two lineages. For example, peptides belonging to the oxytocin/vasopressin family exist in both clades. The same is true for the G protein-coupled receptors (GPCRs) of these peptides. These observations suggest that these neuropeptides and their GPCRs were already present in the common ancestor of Proto- and Deuterostomia, which lived about 700 million years ago (MYA). Furthermore, neuropeptides and their GPCRs occur in two early-branching phyla that diverged before the emergence of Bilateria: Cnidaria (animals like corals and sea anemones), and Placozoa (small disk-like animals, feeding on algae). The sequences of these neuropeptides and their GPCRs, however, are not closely related to those from Bilateria. In addition, cnidarian neuropeptides and their receptors are not closely related to those from Placozoa. We propose that the divergence times between Cnidaria, Placozoa, and Bilateria might be too long for recognizing sequence identities. Leucine-rich repeats-containing GPCRs (LGRs) are a special class of GPCRs that are characterized by a long N-terminus containing 10-20 leucine-rich domains, which are used for ligand binding. Among the ligands for LGRs are dimeric glycoprotein hormones, and insulin-like peptides, such as relaxin. LGRs have been found not only in Proto- and Deuterostomia, but also in early emerging phyla, such as Cnidaria and Placozoa. Humans have eight LGRs. In our current review, we have revisited the annotations of LGRs from the sea anemone Nematostella vectensis and the placozoan Trichoplax adhaerens. We identified 13 sea anemone LGRs and no less than 46 LGRs from T. adhaerens. All eight human LGRs appear to have orthologues in sea anemones and placozoans. LGRs and their ligands, therefore, have a long evolutionary history, going back to the common ancestor of Cnidaria and Placozoa.

The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy.

Background: Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA (KBP). Parathyroid hormone, a G-protein-coupled receptor (GPCR) class B agonist, is an example of the exposure profile being critical to the effect. Since KBP and KBP-A also activate GPCR class B, we compared the effects of injection to continuous infusion of short-acting KBP and long-acting KBP-A in obese and diabetic rats to shed light on the role of exposure profiles. Methods: To explore the metabolic benefits of dose optimization, the following dosing profiles were compared in High Fat Diet (HFD)-fed Sprague–Dawley rats and diabetic Zucker Diabetic Fatty (ZDF) rats: (1) KBP dosed once-daily by injection or by continuous infusion in HFD and ZDF rats; (2) KBP injected once-daily and KBP-A injected once every 3rd day (Q3D) in HFD rats; (3) KBP-A injected Q3D or by infusion in ZDF rats. Results: KBP and KBP-A, delivered by either injection or infusion, resulted in similar weight and food intake reductions in HFD rats. In ZDF rats, injection of KBP improved glucose control significantly compared to infusion, while delivery of KBP-A by injection and continuous infusion was comparable in terms of glucose control. Conclusion: different dosing profiles of KBP and KBP-A had no impact on metabolic benefits in HFD rats. In diabetic ZDF rats, KBP by injection instead of infusion was superior, while for KBP-A the effects were similar.

Functions of regulators of G protein signaling 16 in immunity, inflammation, and other diseases.

Regulators of G protein signaling (RGS) act as guanosine triphosphatase activating proteins to accelerate guanosine triphosphate hydrolysis of the G protein α subunit, leading to the termination of the G protein-coupled receptor (GPCR) downstream signaling pathway. RGS16, which is expressed in a number of cells and tissues, belongs to one of the small B/R4 subfamilies of RGS proteins and consists of a conserved RGS structural domain with short, disordered amino- and carboxy-terminal extensions and an α-helix that classically binds and de-activates heterotrimeric G proteins. However, with the deepening of research, it has been revealed that RGS16 protein not only regulates the classical GPCR pathway, but also affects immune, inflammatory, tumor and metabolic processes through other signaling pathways including the mitogen-activated protein kinase, phosphoinositide 3-kinase/protein kinase B, Ras homolog family member A and stromal cell-derived factor 1/C-X-C motif chemokine receptor 4 pathways. Additionally, the RGS16 protein may be involved in the Hepatitis B Virus -induced inflammatory response. Therefore, given the continuous expansion of knowledge regarding its role and mechanism, the structure, characteristics, regulatory mechanisms and known functions of the small RGS proteinRGS16 are reviewed in this paper to prepare for diagnosis, treatment, and prognostic evaluation of different diseases such as inflammation, tumor, and metabolic disorders and to better study its function in other diseases.