G-protein Coupled Receptor Family Research Articles

Unlocking hope: talquetamab in multiple myeloma treatment: a bispecific breakthrough targeting CD3 and GPRC5D

Multiple myeloma (MM) presents a significant global health burden, with disparities in incidence and outcomes reflecting challenges in recognition and treatment. Talquetamab, a bispecific CD3 T-cell engager targeting G-protein coupled receptor family C group 5 member D (GPRC5D), has emerged as a promising immunotherapy for relapsed/refractory MM (RRMM). In August 2023, talquetamab received accelerated approval from the US FDA for RRMM treatment, followed by conditional marketing authorization from the EMA. Clinical trials demonstrated talquetamab's efficacy, with overall response rates (ORR) of 69% and 76% in heavily pretreated RRMM patients. The phase I monumenTAL-1 trial showcased talquetamab's effectiveness, particularly in high-risk MM and extramedullary disease, with ORRs around 71-74%. Subsequent phase 2 results reaffirmed its efficacy, even in patients with prior T-cell redirection therapies. Combination therapy with daratumumab further enhanced talquetamab's efficacy, addressing concerns of T cell exhaustion. Pharmacokinetic studies revealed sustained responses and manageable adverse events with subcutaneous administration, facilitating convenient dosing regimens. However, talquetamab carries risks of cytokine release syndrome (CRS) and neurologic toxicity, necessitating close monitoring and prompt management. Common adverse events included fever, CRS, musculoskeletal pain, and infections, although severe events were infrequent. Vigilant management strategies, including prophylactic measures and supportive care, mitigate these risks. In conclusion, talquetamab represents a significant advancement in RRMM treatment, offering a promising avenue for T-cell redirection therapy. Ongoing research aims to optimize treatment sequencing and combination strategies, fostering improved outcomes for MM patients. Continued investigation will refine the strategic integration of talquetamab and other immunotherapies, paving the way for enhanced treatment efficacy and patient care in RRMM.

Cardiomyocyte-specific deletion of adhesion G protein-coupled receptor F5 (ADGRF5) increases susceptibility to stress and arrhythmia

G-Protein Coupled Receptors (GPCR) represent the largest family of cell surface receptors in the human body and serve as targets for more than 30% of all approved drugs. Adhesion GPCRs (AGPCR) are an understudied GPCR family containing numerous extracellular domains that interact with extracellular proteins, including many known mediators of cardiac remodeling responses to pathologic stress. However, their relative expression in the heart and impact on cardiac function normally or during disease has been largely unstudied. To address this, we evaluated RNASeq-attained AGPCR expression from left ventricular (LV) samples of adult mice, of which Adgrf5 was one of the most highly expressed. Notably, decreased ADGRF5 expression is observed across numerous failing human LV tissue GEO datasets, and C57BL6/J mice subjected to transaortic constriction (TAC) surgery to induce pressure overload-induced HF also displayed reduced LV Adgrf5 expression by 12 weeks post-TAC. Analysis of published single cell (sc)-RNASeq datasets confirmed Adgrf5 expression in cardiomyocytes (CM), which also decreased following TAC in mice and in CM from failing human hearts. To investigate the impact of CM-specific ADGRF5 on cardiac function and remodeling normally or during disease progression, we crossed floxed ADGRF5 (ADGRF5f/f) and αMHC-Cre mice to generate constitutive, CM-specific ADGRF5 knockout mice (F5cmKO). These mice display normal cardiac structure and function at 12 weeks of age versus αMHC-Cre mice, as assessed via echocardiography, gravimetrics and immunohistochemistry. However, F5cmKO mice develop cardiac dysfunction, maladaptive remodeling, and increased mortality over time, even in the absence of pathologic insult, suggesting a homeostatic function of CM-specific ADGRF5. Following TAC surgery, F5cmKO mice display similar outcomes including enhanced cardiac dysfunction with accelerated remodeling and increased mortality. To attain mechanistic insight into these outcomes, we performed RNA-sequencing on LV tissue of 12-week-old F5cmKO mice, identifying and subsequently validating Scn1b as significantly upregulated in F5cmKO CM. Scn1b encodes for the β subunits of voltage-gated sodium channels (Scnβ1/β1B), which regulate gating and kinetics of Nav1.5 as well as adhesive CM-CM interactions, disruption of which could lead to arrhythmias. Indeed, conscious electrocardiogram (ECG) readings via telemetry indicated F5cmKO mice had a high burden of premature ventricular contractions (PVC), including ventricular tachycardia associated with cardiac enlargement. Using a combination of luciferase and fluorescence resonance energy transfer (FRET) reporters and gene expression analyses in neonatal rat ventricular myocytes (NRVM), we confirmed that ADGRF5 controls Scn1b expression in a Gαq/11 protein-dependent manner. In all, we have discovered that loss of CM-specific ADGRF5 leads to increased Scn1b expression with enhanced susceptibility to stress, arrythmias and sudden death, thus may provide a novel GPCR target to promote the maintenance of cardiac rhythm. AHA Predoctoral Fellowship 834906 to J.M.E. P01 HL147841 to D.T. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Stepwise activation of a metabotropic glutamate receptor.

Metabotropic glutamate receptors belong to a family of Gprotein-coupled receptors that are obligate dimers and possess a large extracellular ligand-binding domain that is linked via a cysteine-rich domain to their 7-transmembrane domain1. Upon activation, these receptors undergo a large conformational change to transmit the ligand binding signal from the extracellular ligand-binding domain to the Gprotein-coupling 7-transmembrane domain2. In this manuscript, we propose a model for a sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5. We present a series of structures in lipid nanodiscs, from inactive to fully active, including agonist-bound intermediate states. Further, using bulk and single-molecule fluorescence imaging, we reveal distinct receptor conformations upon allosteric modulator and Gprotein binding.

Bispecific antibodies for the treatment of relapsed/refractory multiple myeloma: updates and future perspectives.

Patients with relapsed/refractory multiple myeloma (RRMM) that are refractory to the five most active anti-MM drugs, so-called penta-refractory MM, have historically had dismal outcomes with subsequent therapies. Progressive immune dysfunction, particularly of the T-cell repertoire, is implicated in the development of disease progression and refractory disease. However, the advent of novel immunotherapies such as bispecific antibodies are rapidly changing the treatment landscape and improving the survival outcomes of patients with RRMM. Bispecific antibodies are antibodies that are engineered to simultaneously engage cytotoxic immune effector cells (T cells or NK cells) and malignant plasma cells via binding to immune effector cell antigens and extracellular plasma cell antigens leading to immune effector cell activation and malignant plasma cell destruction. Currently, bispecific antibodies that bind CD3 on T cells and plasma cell epitopes such as B-cell maturation antigen (BCMA), G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5) are the most advanced in clinical development and are showing unprecedented response rates in patients with RRMM, including patients with penta-refractory disease. In this review article, we explore the available clinical data of bispecific antibodies in RRMM and summarize the efficacy, safety, toxicity, clinical outcomes, mechanisms of resistance, and future directions of these therapies in patients with RRMM.

Local anesthetics inhibit muscarinic acetylcholine receptor-mediated calcium responses and the recruitment of β-arrestin in HSY human parotid cells

ObjectivesLocal anesthetics act on G protein-coupled receptors (GPCRs); thus, their potential as allosteric modulators of GPCRs has attracted attention. Intracellular signaling via GPCRs involves both G-protein- and β-arrestin-mediated pathways. To determine the effects of local anesthetics on muscarinic acetylcholine receptors (mAChR), a family of GPCRs, we analyzed the effects of local anesthetics on mAChR-mediated Ca2+ responses and formation of receptor–β-arrestin complexes in the HSY human parotid cell line. MethodsCa2+ responses were monitored by fura-2 spectrofluorimetry. Ligand-induced interactions between mAChR and β-arrestin were examined using a β-arrestin GPCR assay kit. ResultsLidocaine reduced mAChR-mediated Ca2+ responses but did not change the intracellular Ca2+ concentration in non-stimulated cells. The membrane-impermeant lidocaine analog QX314 and procaine inhibited mAChR-mediated Ca2+ responses, with EC50 values of 48.0 and 20.4 μM, respectively, for 50 μM carbachol-stimulated Ca2+ responses. In the absence of extracellular Ca2+, the pretreatment of cells with QX314 reduced carbachol-induced Ca2+ release, indicating that QX314 reduced Ca2+ release from intracellular stores. Lidocaine and QX314 did not affect store-operated Ca2+ entry as they did not alter the thapsigargin-induced Ca2+ response. QX314 and procaine reduced the carbachol-mediated recruitment of β-arrestin, and administration of procaine suppressed pilocarpine-induced salivary secretion in mice. ConclusionLocal anesthetics, including QX314, act on mAChR to reduce carbachol-induced Ca2+ release from intracellular stores and the recruitment of β-arrestin. These findings support the notion that local anesthetics and their derivatives are starting points for the development of functional allosteric modulators of mAChR.

Unveiling the therapeutic prospects of EGFR inhibition in rotenone-mediated parkinsonism in rats: Modulation of dopamine D3 receptor

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The dopamine D3 receptor (D3R) plays a significant role in the pathogenesis and treatment of PD. Activation of receptor tyrosine kinases (RTKs) inhibits signaling mediated by G protein-coupled receptor (GPCR). Epidermal growth factor receptors (EGFRs) and dopamine D3 receptors in the brain are directly associated with PD, both in terms of its development and potential treatment. Therefore, we investigated the impact of modulating the EGFR, a member of the RTKs family, and the dopamine D3R, a member of the GPCR family. In the present study, 100 mg/kg of lapatinib (LAP) was administered to rotenone-intoxicated rats for three weeks. Our findings indicate that LAP effectively alleviated motor impairment, improved histopathological abnormalities, and restored dopaminergic neurons in the substantia nigra. This restoration was achieved through the upregulation of dopamine D3R and increase of tyrosine hydroxylase (TH) expression, as well as boosting dopamine levels. Furthermore, LAP inhibited the activity of p-EGFR, GRK2, and SCR. Additionally, LAP exhibited antioxidant properties by inhibiting the 4-hydroxynonenal (4-HNE) and PLCγ/PKCβII pathway, while enhancing the antioxidant defense mechanism by increasing GSH-GPX4 pathway. The current study offers insights into the potential repositioning of LAP as a disease-modifying drug for PD. This could be achieved by modulating the dopaminergic system and curbing oxidative stress.

Knockout of formyl peptide receptor 1 reduces osteogenesis and bone healing

AimsFormyl peptide receptor 1 (FPR1), from a G-protein coupled receptor family, was previously well-characterized in immune cells. But the function of FPR1 in osteogenesis and fracture healing was rarely reported. This study, using the FPR1 knockout (KO) mouse, is one of the first studies that try to investigate FPR1 function to osteogenic differentiation of bone marrow-derived stem cells (BMSCs) in vitro and bone fracture healing in vivo. Materials and methodsPrimary BMSCs were isolated from both FPR1 KO and wild type (WT) mice. Cloned mouse BMSCs (D1 cells) were used to examine role of FoxO1 in FPR1 regulation of osteogenesis. A closed, transverse fracture at the femoral midshaft was created to compare bone healing between KO and WT mice. Biomechanical and structural properties of femur were compared between healthy WT and KO mice. Key findingsFPR1 expression increased significantly during osteogenesis of both primary and cloned BMSCs. Compared to BMSCs from FPR1 KO mice, WT BMSCs displayed considerably higher levels of osteogenic markers as well as mineralization. Osteogenesis by D1 cells was inhibited by either an FPR1 antagonist cFLFLF or a specific inhibitor of FoxO1, AS1842856. In addition, the femur from WT mice had better biomechanical properties than FPR1 KO mice. Furthermore, bone healing in WT mice was remarkably improved compared to FPR1 KO mice analyzed by X-ray and micro-CT. SignificanceThese findings indicated that FPR1 played a vital role in osteogenic differentiation and regenerative capacity of fractured bone, probably through the activation of FoxO1 related signaling pathways.

ADGRG1, an adhesion G protein-coupled receptor, forms oligomers.

G protein-coupled receptor (GPCR) oligomerization is a highly debated topic in the field. While initially believed to function as monomers, current literature increasingly suggests that these cell surface receptors, spanning almost all GPCR families, function as homo- or hetero-oligomers. Yet, the functional consequences of these oligomeric complexes remain largely unknown. Adhesion GPCRs (aGPCRs) present an intriguing family of receptors characterized by their large and multi-domain N-terminal fragments (NTFs), intricate activation mechanisms, and the prevalence of numerous splice variants in almost all family members. In the present study, bioluminescence energy transfer (BRET) and Förster resonance energy transfer (FRET) were used to study the homo-oligomerization of adhesion G protein-coupled receptor G1 (ADGRG1; also known as GPR56) and to assess the involvement of NTFs in these receptor complexes. Based on the results presented herein, we propose that ADGRG1 forms 7-transmembrane-driven homo-oligomers on the plasma membrane. Additionally, Stachel motif interactions appear to influence the conformation of these receptor complexes.

Evaluating conserved domains and motifs of decapod gonadotropin-releasing hormone G protein-coupled receptor superfamily.

G protein-coupled receptors (GPCRs) are an ancient family of signal transducers that are both abundant and consequential in metazoan endocrinology. The evolutionary history and function of the GPCRs of the decapod superfamilies of gonadotropin-releasing hormone (GnRH) are yet to be fully elucidated. As part of which, the use of traditional phylogenetics and the recycling of a diminutive set of mis-annotated databases has proven insufficient. To address this, we have collated and revised eight existing and three novel GPCR repertoires for GnRH of decapod species. We developed a novel bioinformatic workflow that included clustering analysis to capture likely GnRH receptor-like proteins, followed by phylogenetic analysis of the seven transmembrane-spanning domains. A high degree of conservation of the sequences and topology of the domains and motifs allowed the identification of species-specific variation (up to ~70%, especially in the extracellular loops) that is thought to be influential to ligand-binding and function. Given the key functional role of the DRY motif across GPCRs, the classification of receptors based on the variation of this motif can be universally applied to resolve cryptic GPCR families, as was achieved in this work. Our results contribute to the resolution of the evolutionary history of invertebrate GnRH receptors and inform the design of bioassays in their deorphanization and functional annotation.

Decrypting orphan GPCR drug discovery via multitask learning

The drug discovery of G protein-coupled receptors (GPCRs) superfamily using computational models is often limited by the availability of protein three-dimensional (3D) structures and chemicals with experimentally measured bioactivities. Orphan GPCRs without known ligands further complicate the process. To enable drug discovery for human orphan GPCRs, multitask models were proposed for predicting half maximal effective concentrations (EC50) of the pairs of chemicals and GPCRs. Protein multiple sequence alignment features, and physicochemical properties and fingerprints of chemicals were utilized to encode the protein and chemical information, respectively. The protein features enabled the transfer of data-rich GPCRs to orphan receptors and the transferability based on the similarity of protein features. The final model was trained using both agonist and antagonist data from 200 GPCRs and showed an excellent mean squared error (MSE) of 0.24 in the validation dataset. An independent test using the orphan dataset consisting of 16 receptors associated with less than 8 bioactivities showed a reasonably good MSE of 1.51 that can be further improved to 0.53 by considering the transferability based on protein features. The informative features were identified and mapped to corresponding 3D structures to gain insights into the mechanism of GPCR-ligand interactions across the GPCR family. The proposed method provides a novel perspective on learning ligand bioactivity within the diverse human GPCR superfamily and can potentially accelerate the discovery of therapeutic agents for orphan GPCRs.

Free fatty acid receptors beyond fatty acids: A computational journey to explore peptides as possible binders of GPR120

Free fatty acids receptors, with members among G protein-coupled receptors (GPCRs), are crucial for biological signaling, including the perception of the so called “fatty taste”. In recent years, GPR120, a protein belonging to the GPCR family, drew attention as an interesting pharmacological target to cope with obesity, satiety and diabetes. Apart from long chain fatty acids, which are GPR120 natural agonists, other synthetic molecules were identified as agonists expanding the chemical space of GPR120's ligands. In this scenario, we unveiled peptides as possible GPR120 binders toward a better understanding of this multifaceted and relevant target. This study analyzed a virtual library collecting 531 441 low-polar hexapeptides, providing mechanistic insights on the GPR120 activation and further extending the possible chemical space of GPR120 agonists. The computational pipeline started with a narrow filtering of hexapeptides based on their chemical similarity with known GPR120 agonists. The best hits were tested through docking studies, molecular dynamics and umbrella sampling simulations, which pointed to G[I,L]FGGG as a promising GPR120 agonist sequence. The presence of both peptides in food-related proteins was thoroughly assessed, revealing they may occur in mushrooms, food-grade bacteria and rice. Simulations on the counterparts with D-amino acids were also performed. Umbrella sampling simulations described that GdIFGGG may have a better interaction compared to its all-L counterpart (−13 kCal/mol ΔG and −6 kCal/mol ΔG, respectively). Overall, we obtained a predictive model to better understand the underpinning mechanism of GPR120-hexapeptides interaction, hierarchizing novel potential agonist peptides for further analysis and describing promising food sources worth of further dedicated investigations.

Pooled Analysis on Bispecific Antibody-Related Toxicities in Multiple Myeloma

Background: Multiple myeloma (MM) is a hematologic malignancy caused by the uncontrolled proliferation of malignant plasma cells in the bone marrow. Bispecific antibodies (BsAbs) are a new novel class of drugs currently assessed in the setting of relapsed/refractory MM (RRMM), with impressive outcomes. BsAbs are designed to direct against specific antigenic epitopes on the surface of malignant plasma cells, with two main categories: B-cell maturation antigen (BCMA) or other (non-BCMA) antigens which include G-protein coupled receptor family C group 5 member D (GPRC5D) and Fc Receptor-Like 5 (FcRH5). Methods: We conducted a pooled analysis of the available literature on BsAbs reported in the form of abstract or full peer-reviewed publications, published until June 2023, using PubMed, Scopus, Google Scholar and Embase databases. BsAbs were classified into two groups: BCMA and non-BCMA-directed agents. Studies on BsAbs used in combination with other plasma-cell directed agents, and studies reporting outcomes of patients who had prior exposure of other BsAbs were excluded. BsAb included in our study were the following: Teclistamab, Elranatamab, REGN-5458, AMG420, AMG701, CC-93269, TNB-383B, Linvoseltamab, Talquetamab, and Cevostamab. We collected safety data including cytokine release syndrome (CRS), neurotoxicity, infections rates and hematologic toxicities. We used T-test statistics to determine significance (p-value<0.05) and comparisons between the BCMA and non-BCMA groups. Results: A total of 1926 patients with RRMM treated with BsAbs were included in this analysis. Among them, 1288 (66.7%) received a BCMA-directed BsAbs, while 638 (33.1%) received a non-BCMA-directed bsAb. Patient baseline characteristics including prior lines of therapy (LOT), and refractoriness status were comparable between the two groups. The median age of the entire cohort was 63 years and had a median of 5 prior LOT. Median follow-up duration was 5.35 and 5.6 months for the patients treated with BCMA agents and non-BCMA agents, respectively. CRS was reported in 59.6% of all patients, infections in 50%, neutropenia in 41.86%, anemia in 37.32%, and lymphopenia in 36.41%. For grade 3-4 adverse events (AEs), the percentages were as follows: CRS 22.9%, infections 21.46%, neutropenia 38.12%, and anemia 25.37%. Non-BCMA-targeting BsAbs showed no significant difference in all grade and type hematologic toxicities (neutropenia, anemia, lymphopenia, leukopenia, and thrombocytopenia combined) compared to BCMA-targeting BsAbs (p=0.57). However, a significant difference was observed when comparing BCMA-targeting to non-BCMA-targeting BsAbs in terms of combined grade 3-4 hematologic toxicity (p=0.0002). In addition, the group of patients who received BCMA-targeting BsAbs had significantly worse hypogammaglobulinemia compared to patients treated with non-BCMA BsAbs (p=0.006). The overall CRS rate (all grades) was significantly higher in non-BCMA BsAbs (p<0.0001), however, both groups experienced similar grade 3-4 CRS rates. Neurotoxicity rates were also similar between the two groups (p=0.067). Conclusion: The use of BsAbs in MM has demonstrated remarkable efficacy; however, these have been linked to a unique adverse event profile. Our results showed that non-BCMA bsAb were associated less hematotoxicity (combined grade 3-4 events and hypogammaglobulinemia), whereas BCMA bsAb were associated with less CRS rates. This is important information for treatment selection and mitigation strategy development aiming to optimize patient outcomes.

Regulation Mechanism of Dopamine Receptor 1 in Low Temperature Response of Marsupenaeus japonicus.

Dopamine receptors (DARs) are important transmembrane receptors responsible for receiving extracellular signals in the DAR-mediated signaling pathway, and are involved in a variety of physiological functions. Herein, the D1 DAR gene from Marsupenaeus japonicus (MjDAD1) was identified and characterized. The protein encoded by MjDAD1 has the typical structure and functional domains of the G-protein coupled receptor family. MjDAD1 expression was significantly upregulated in the gills and hepatopancreas after low temperature stress. Moreover, double-stranded RNA-mediated silencing of MjDAD1 significantly changed the levels of protein kinases (PKA and PKC), second messengers (cyclic AMP (cAMP), cyclic cGMP, calmodulin, and diacyl glycerol), and G-protein effectors (adenylate cyclase and phospholipase C). Furthermore, MjDAD1 silencing increased the apoptosis rate of gill and hepatopancreas cells. Thus, following binding to their specific receptors, G-protein effectors are activated by MjDAD1, leading to DAD1-cAMP/PKA pathway-mediated regulation of caspase-dependent mitochondrial apoptosis. We suggest that MjDAD1 is indispensable for the environmental adaptation of M. japonicus.

Lack of evidence for coevolution between oxytocin receptor N-terminal variants and monogamy in placental mammals

Oxytocin (OXT) is a neurohypophyseal hormone that influences a wide range of affiliative behaviors, such as pair-bonding and infant care, across mammals. The effects of OXT depend significantly on an adequate interaction with its receptor, OXTR. OXTR belongs to the G-protein coupled receptor family. The extracellular N-terminal domain of OXTR interacts with the linear C-terminal tail of OXT and is required for OXT binding. Across mammalian species there is a genetic diversity in OXTR terminal sequence. Previous work on primates has shown an association between OXTR phylogeny and monogamy. However, it is not clear whether this variation coevolved with either mating system (monogamy) or infant care behaviors (such as allomaternal care). Here, we take a phylogenetic comparative and evolutionary modeling approach across a wide range of placental mammals (n = 60) to test whether OXTR N-terminal variants co-evolved with either monogamy or allomaternal care behaviors. Our results indicate that the diversity in OXTR N-terminal region is unlikely to provide the underlying genetic bases for variation in mating system and/or allomaternal behavior as we find no evidence for co-evolution between protein sequence and affiliative behaviors. Hence, the role played by OXT in influencing affiliative behaviors is unlikely to be mediated by the genetic diversity of its receptor.

Recent Studies on Serotonin 5-HT2A Receptor Antagonists in Medicinal Chemistry: A Last Decades Survey.

In the last decades, much attention has been paid to the functioning of receptors to understand better how they work with various chemical motifs. Among different families, G-proteincoupled receptor (GPCR) families have drawn much attention in the twenty-first century. They are the most prominent signal transducer across the cell membrane, comprising thousand-odd proteins. One of the members of GPCRs is the serotonin 2A (5-HT2A) receptor, which has been associated with complex etiological mental illnesses. In this survey, we collected data on 5-HT2A, i.e., the role of 5- HT2A receptors in human and animal analogy, various binding site functionalities, advanced effects, and synthetic aspects.

Talquetamab: First Approval.

Talquetamab (talquetamab-tgvs; TALVEY®), a humanized, bispecific G-protein coupled receptor family C group 5 member D (GPRC5D)-directed CD3 T-cell engager, is being developed by Janssen for the treatment of multiple myeloma (MM). In early August 2023, talquetamab was granted accelerated approval in the USA for the treatment of adults with relapsed or refractory MM (RRMM) and in late August 2023, talquetamab was granted conditional marketing authorisation in the EU for the treatment of adult patients with RRMM. This article summarizes the milestones in the development of talquetamab leading to this first approval for RRMM.

Allosteric modulation of the fish taste receptor type 1 (T1R) family by the extracellular chloride ion

Many G protein-coupled receptors (GPCRs) are allosterically modulated by inorganic ions. Although the intraoral ionic composition of the oral cavity varies depending on the living environment and feeding behavior, little is known about whether and how it affects the function of taste receptor type 1 (T1R), a member of the class C GPCR family. Here, we report that chloride ions allosterically modulate the functions of specific fish T1Rs, namely, mfT1R2a/mfT1R3 and zfT1R2a/zfT1R3. Site-directed mutagenesis revealed mfT1R2a K265, which lies in the extracellular domain of mfT1R2a, to be as a critical residue for the modulation of mfT1R2a/mfT1R3 by Cl−. However, this residue is not conserved in zfT1R2a, and the introduction of the key residue at the corresponding site of another T1R, mfT1R2b, did not confer Cl− susceptibility. These results indicate the variability of the determinants of Cl− susceptibility.

Activation of PI3K/Akt pathway by G protein-coupled receptor 37 promotes resistance to cisplatin-induced apoptosis in non-small cell lung cancer.

Lung cancer is a major public health concern and represents the most common cause of cancer-related death worldwide. Among eukaryotes, the G protein-coupled receptor (GPCR) family stands as the largest group of membrane proteins. Alterations in GPCR gene expression and dysregulation of signal transduction have been recognized as the markers of malignancy. As a member of the GPCR family, G protein-coupled receptor 37 (GPR37) exhibits unknown functions in tumors, particularly in non-small-cell lung cancer (NSCLC) METHODS: We explored the expression and prognosis of GPR37 in NSCLC through TCGA, GTEx, GEO, and GEPIA2. We detected the expression of GPR37 in NSCLC tissues and cell lines. The study explored the influence of GPR37 on tumor cell proliferation. Furthermore, we examined the effects of GPR37 on tumor cell apoptosis and invasion. Most importantly, we investigated whether GPR37 affects cisplatin-induced drug resistance in NSCLC. Furthermore, by conducting animal experiments, we assessed the impact of GPR37 on NSCLC and delved into underlying mechanisms. (1) In NSCLC, the expression of GPR37 is markedly higher than that in corresponding normal tissues. We found that elevated GPR37 expression predicts an unfavorable prognosis. (2) It was demonstrated that GPR37 positively regulates NSCLC cell invasion, migration, and proliferation, suppresses cell apoptosis, heightens resistance to cisplatin, and promotes tumor formation and growth. Conversely, we observed that GPR37 knockdown suppresses NSCLC cell invasion, migration, and proliferation, promotes cell apoptosis, increases sensitivity to cisplatin, and affects tumor formation and growth. (3) GPR37 activates PI3K/Akt/mTOR signal transduction pathways to mediate epithelial-mesenchymal transition (EMT), thereby promoting the progression of NSCLC. It was suggested that GPR37 acts a crucial role in promoting the occurrence and development of NSCLC. Knockdown of GPR37 significantly inhibits the occurrence and development of NSCLC. Therefore, our findings demonstrated that GPR37 may represent a viable therapeutic target for NSCLC.

GPRC5C drives branched-chain amino acid metabolism in leukemogenesis

AbstractLeukemia stem cells (LSCs) share numerous features with healthy hematopoietic stem cells (HSCs). G-protein coupled receptor family C group 5 member C (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) is yet to be determined. Within patient AML cohorts, high GPRC5C levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression through the activation of NF-κB, which resulted in an altered metabolic state with increased levels of intracellular branched-chain amino acids (BCAAs). This onco-metabolic profile was reversed upon loss of Gprc5c, which also abrogated the leukemia-initiating potential. Targeting the BCAA transporter SLC7A5 with JPH203 inhibited oxidative phosphorylation and elicited strong antileukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow cells. This antileukemia effect was strengthened in the presence of venetoclax and azacitidine. Our results indicate that the GPRC5C–NF-κB-SLC7A5–BCAAs axis is a therapeutic target that can compromise leukemia stem cell function in AML.

RNAi-Mediated Interference with EonuGR1 Affects the Recognition of Phenylacetaldehyde by Empoasca onukii Matsuda (Hemiptera: Cicadellidae)

Empoasca onukii Matsuda is a primary pest of the tea plant Camellia sinensis (L.) O. Ktze that severely influences the production and quality of tea products. Gustatory receptors (GRs) are an indispensable part of the E. onukii chemosensory machinery as members of the G-protein coupled receptor family. Insect odor and gustatory receptors are consumingly sensitive and selective sensory receptors to search for foraging, mates, and spawning sites. In this study, the gustatory receptor EonuGR1 was cloned and analyzed bioinformatically, and the expression levels of EonuGR1 in diverse tissues of E. onukii were tested via qRT-PCR. The behavioral response of E. onukii to volatile compounds was determined via RNA interference and Y-tube olfactometer assays to investigate the role of EonuGR1 in the olfactory recognition of E. onukii. The coding sequence length of EonuGR1 was 1062 bp, and the length of the protein encoded by EonuGR1 was 40.52 kD. The highest interference efficiency was observed after 3 h of dsEonuGR1 treatment via root soak treatment. Moreover, the response rates to phenylacetaldehyde at concentrations of 10 and 0.1 µL/mL were significantly downregulated in E. onukii. The responses to phenylacetaldehyde at concentrations of 10 and 100 µL/mL showed a significant decrease after dsEonuGR1 treatment for 12 h in E. onukii. In conclusion, EonuGR1 was highly expressed in the abdomen and functioned in olfactory recognition of the tea plant volatile phenylacetaldehyde by E. onukii. Overall, EonuGR1 has the potential as a gene target for the design of effective control strategies against E. onukii.