Article
Chemistry, Medicinal
Toni Kline, Cong Xu, Faith R. Kreitzer, Dow P. Hurst, Khalil M. Eldeeb, Jim Wager-Miller, Kathleen Olivas, Seon A. Hepburn, John W. Huffman, Ken Mackie, Allyn C. Howlett, Patricia Reggio, Nephi Stella
Summary: The author synthesized fourteen novel alkylindole analogues and evaluated their activities at alkylindole-sensitive GPCRs. They found three characteristics that favor binding to alkylindole-sensitive GPCRs versus CB1R/CB2R and identified novel chemical tools for studying alkylindole-sensitive GPCRs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Karim Nagi, H. Ongun Onaran
Summary: GPCRs are the largest family of approved therapeutic targets, with ligands stimulating these receptors often causing undesired side effects. Biased agonism offers potential for improving therapeutic responses, but the identification and quantification of biased agonists remain challenging.
CELLULAR SIGNALLING
(2021)
Review
Endocrinology & Metabolism
Fanhua Wang, Mingyao Liu, Ning Wang, Jian Luo
Summary: This review discusses the role of G-protein coupled receptors (GPCRs) in osteoarthritis (OA), including the pathophysiological processes involved, preclinical and clinical trial data, and the challenges in developing therapies targeting GPCRs for OA.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Review
Pharmacology & Pharmacy
Kate F. Byrne, Ajay Pal, James F. Curtin, John C. Stephens, Gemma K. Kinsella
Summary: The focus of the review is on G-protein-coupled receptor (GPCR) targets, with chemokine, cannabinoid, and dopamine receptors showing promise. Further research is needed on potential targets such as MC4R, adhesion receptors, LPA, and Smo receptors to develop new drug-screening strategies for safe and effective GBM therapies.
DRUG DISCOVERY TODAY
(2021)
Review
Biochemistry & Molecular Biology
Dekel David, Ziv Bentulila, Merav Tauber, Yair Ben-Chaim
Summary: GPCRs are involved in signal transduction processes, and although they span the cell membrane, they have not been considered to be regulated by membrane potential. Recent studies, however, have shown that several GPCRs are voltage regulated. This review discusses the advances in understanding the voltage dependence of GPCRs, the suggested molecular mechanisms, and the possible physiological roles.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biology
Ramon Cierco Jimenez, Nil Casajuana-Martin, Adrian Garcia-Recio, Lidia Alcantara, Leonardo Pardo, Mercedes Campillo, Angel Gonzalez
Summary: The study analyzed 119,069 natural variants in human olfactory receptors, revealing a significant diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a considerable number of changes occurring at the structurally conserved regions. Mutations in positions linked to the conserved GPCR activation mechanism were highlighted, which could imply phenotypic variation in olfactory perception.
Review
Pharmacology & Pharmacy
Sergi Ferre, Francisco Ciruela, Carmen W. Dessauer, Javier Gonzalez-Maeso, Terence E. Hebert, Ralf Jockers, Diomedes E. Logothetis, Leonardo Pardo
Summary: The study proposes the concept of GPCR-effect assemblies (GEMMAs), which are pre-assembled before receptor activation and allow more efficient interactions between specific signaling components. This offers an alternative model to the conventional collision coupling model and explains the differential properties of GPCRs in different cellular environments.
PHARMACOLOGY & THERAPEUTICS
(2022)
Review
Chemistry, Multidisciplinary
Xin-heng He, Chong-zhao You, Hua-liang Jiang, Yi Jiang, H. Eric Xu, Xi Cheng
Summary: G protein-coupled receptors (GPCRs) are important drug targets that play crucial roles in various physiological processes. Although extensive efforts have been made in the field of structural biology, a significant number of GPCR structures remain unsolved due to their structural instability. Recently, AlphaFold2 has been developed as a tool to predict the structure models of GPCRs and other functionally important proteins. However, our evaluation reveals several differences between the predicted models and experimental structures, such as the assembly of domains, shape of ligand-binding pockets, and conformation of binding interfaces. These differences hinder the use of predicted structure models in functional studies and structure-based drug design, where reliable high-resolution structural information is required.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Biochemistry & Molecular Biology
Wojciech Pietrus, Rafal Kurczab, Dagmar Stumpfe, Andrzej J. Bojarski, Juergen Bajorath
Summary: The study showed that introducing fluorine can significantly increase ligand potency, but the effect of fluorination on affinity varies depending on the fluorination position. Fluorination of the aromatic ring at the ortho position is favorable for potency enhancement, while fluorination of aliphatic fragments more often leads to a decrease in biological activity.
Review
Immunology
Emilia Diaz, Anthony Febres, Michelle Giammarresi, Adrian Silva, Oriana Vanegas, Carlos Gomes, Alicia Ponte-Sucre
Summary: Detection and transduction of environmental signals are crucial for successful parasite invasion, and Leishmania uses diverse molecules for inter-cellular signaling. While G protein-coupled receptors (GPCRs) and their related transduction mechanisms play an important role in this process, canonical GPCR-related signal transduction systems have not been found in Leishmania, although reduced versions have been identified in Trypanosomatidae. These inter-cellular communication systems are essential for the survival of multicellular and unicellular organisms.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Yunfang Xiong, Ran Ke, Qingyu Zhang, Wenjun Lan, Wanjun Yuan, Karol Nga Ieng Chan, Tom Roussel, Yifan Jiang, Jing Wu, Shuai Liu, Alice Sze Tsai Wong, Joong Sup Shim, Xuanjun Zhang, Ruiyu Xie, Nelson Dusetti, Juan Iovanna, Nagy Habib, Ling Peng, Leo Tsz On Lee
Summary: This study reports the effective modulation of a GPCR for cancer treatment using small activating RNAs (saRNAs) for the first time. The saRNAs promote the expression of MAS1, a GPCR that counteracts cancer cell proliferation and migration. By enhancing MAS1 expression, these saRNAs suppress tumorigenesis and inhibit tumor progression in multiple cancer models. This research not only provides a new strategy for cancer therapy by targeting the renin-angiotensin system, but also offers a new avenue to modulate GPCR signaling through RNA activation.
Review
Engineering, Biomedical
Yuhong Jiang, Yuke Li, Xiujuan Fu, Yue Wu, Rujing Wang, Mengnan Zhao, Canquan Mao, Sanjun Shi
Summary: The translation article introduces the interaction between G protein-coupled receptors (GPCRs) and nanotechnology, as well as how nanotechnology can improve the efficacy and safety of GPCR-related drugs. Nanotechnology can encapsulate GPCR ligands to construct synthetic nano-GPCRs and precisely initiate sustained endosomal signal transduction through nanoparticles. Moreover, nanoparticles can enhance the potency of delivery systems by actively targeting specific cells through ligand-receptor binding and receptor-dependent endocytosis.
ACTA BIOMATERIALIA
(2023)
Article
Medicine, Research & Experimental
Tatsuya Ihara, Youichi Shinozaki, Eiji Shigetomi, Yosuke Danjo, Sachiko Tsuchiya, Mie Kanda, Manabu Kamiyama, Masayuki Takeda, Schuichi Koizumi, Takahiko Mitsui
Summary: In this study, GPR55 was found to be predominantly expressed in bladder urothelial cells. The results showed that PEA could induce the release of Ca2+ and stimulate the release of NGF and PGI2 in urothelial cells, leading to micturition reflex activation and nocturia.
Article
Biochemistry & Molecular Biology
Jingshi Liu, Yongdong Niu, Bin Zhang, Qisi Sun, Haiyi Li, Lu Bai, Zhongjing Su
Summary: The expression levels of GPER1 are found to be associated with tumor type and survival rates in esophageal carcinoma. In overall esophageal carcinoma, low expression of GPER1 is correlated with poor survival rates, while overexpression of GPER1 is associated with the development of esophageal adenocarcinoma and its pre-cancerous lesion. Furthermore, the protein expression of GPER1 is higher in esophageal adenocarcinoma tissues compared to normal esophageal tissues, whereas it is lower in esophageal squamous cell carcinoma tissues.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cardiac & Cardiovascular Systems
Alyssa Grogan, Emilio Y. Lucero, Haoran Jiang, Howard A. Rockman
Summary: G protein-coupled receptors (GPCRs) play key roles in cardiac health and disease, and are targeted for the treatment of cardiovascular diseases. Recent advancements in understanding GPCR signaling, regulation, and pharmacological properties have provided valuable insights.
CARDIOVASCULAR RESEARCH
(2023)
Article
Neurosciences
Carlos Costas-Insua, Manuel Guzman
Summary: High-grade gliomas are the most common and aggressive form of primary brain cancer in adults. Activating cannabinoid receptors can inhibit glioma cells and affect the tumor microenvironment, but the exact role of the endocannabinoid system in glioma remains largely unknown.
Article
Cell Biology
Anibal Sanchez-de la Torre, Tania Aguado, Alba Huerga-Gomez, Silvia Santamaria, Antonietta Gentile, Juan Carlos Chara, Carlos Matute, Krisztina Monory, Susana Mato, Manuel Guzman, Beat Lutz, Ismael Galve-Roperh, Javier Palazuelos
Summary: The study reveals that cannabinoids through CB1 receptors play a crucial role in modulating oligodendrocyte precursor cell differentiation and postnatal CNS myelination, possibly by regulating the RhoA/ROCK signaling pathway. Pharmacological activation of CB1 receptors promotes oligodendrocyte development and CNS myelination, while pharmacological inactivation of ROCK overcomes CB1 receptor deficiency-related defects.
CELL DEATH & DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Jose Luis Marin-Rubio, Laura Vela-Martin, Jack Gudgeon, Eduardo Perez-Gomez, Frances R. Sidgwick, Matthias Trost, Debbie L. Cunningham, Javier Santos, Jose Fernandez-Piqueras, Maria Villa-Morales
Summary: A reduction in FADD levels has been found in precursor T-cell neoplasms, which may affect tumor cell apoptosis and lead to poor clinical outcomes. FADD is involved in both apoptotic and non-apoptotic functions, and its expression could serve as a prognostic marker and guide targeted therapeutic strategies in these tumors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Monica Fernandez-Cortes, Daniel Delgado-Bellido, Eloisa Bermudez-Jimenez, Jesus M. Paramio, Francisco O'Valle, Stefan Vinckier, Peter Carmeliet, Angel Garcia-Diaz, F. Javier Oliver
Summary: Vasculogenic mimicry (VM) refers to the ability of aggressive tumor cells to develop pseudovascular structures without endothelial cells. This study investigated the role of hypoxia and PARP inhibition in VM. Results showed that the PARP inhibitor olaparib improved pericyte coverage and reduced metastasis in uveal melanoma xenografts with VM. PARP inhibition and hypoxia induced changes in melanoma tube formation and gene expression related to vasculogenesis, enhancing the endothelial-like phenotype of VM+ melanoma cells. Overall, PARP inhibitors have the potential to modulate VM characteristics and reduce metastatic spread in melanoma.
JOURNAL OF PATHOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Maria Villa-Morales, Laura Perez-Gomez, Eduardo Perez-Gomez, Pilar Lopez-Nieva, Pablo Fernandez-Navarro, Javier Santos
Summary: The standard-of-care treatment for T-cell acute lymphoblastic leukaemia (T-ALL) achieves reasonable response rates, but relapsed or treatment-resistant patients have poor outcomes. This study explores the potential of NRF2 activation as a prognostic biomarker in T-ALL. Through analysis of transcriptomic, genomic, and clinical data, high NFE2L2 levels were found to be associated with shorter overall survival in T-ALL patients. The PI3K-AKT-mTOR pathway plays a role in the oncogenic signaling induced by NRF2 in T-ALL. High NFE2L2 levels are also associated with drug resistance in T-ALL, possibly due to NRF2-induced glutathione biosynthesis. These findings suggest that NFE2L2 levels could be a predictive biomarker for poor treatment response in T-ALL patients, offering insights for improved patient stratification and targeted therapies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Irene B. Maroto, Carlos Costas-Insua, Coralie Berthoux, Estefania Moreno, Andrea Ruiz-Calvo, Carlos Montero-Fernandez, Andrea Macias-Camero, Ricardo Martin, Nuria Garcia-Font, Jose Sanchez-Prieto, Giovanni Marsicano, Luigi Bellocchio, Enric I. Canela, Vicent Casado, Ismael Galve-Roperh, Angel Nunez, David Fernandez de Sevilla, Ignacio Rodriguez-Crespo, Pablo E. Castillo, Manuel Guzman
Summary: The interaction between CB1R and GAP43 affects the signaling of excitatory synapses in the brain, thereby inhibiting the anti-convulsant activity of cannabinoids.
NATURE COMMUNICATIONS
(2023)
Article
Oncology
Carlos Costas-Insua, Marta Seijo-Vila, Cristina Blazquez, Sandra Blasco-Benito, Francisco Javier Rodriguez-Baena, Giovanni Marsicano, Eduardo Perez-Gomez, Cristina Sanchez, Berta Sanchez-Laorden, Manuel Guzman
Summary: Based on in vitro and in silico experiments, it has been discovered that the cannabinoid CB1 receptor regulates the proliferation of melanoma brain metastases. This finding provides a new perspective for further research on melanoma brain metastases.
Article
Neurosciences
Marc Espina, Nadia Di Franco, Martina Branas-Navarro, Irene Rodriguez Navarro, Veronica Brito, Laura Lopez-Molina, Carlos Costas-Insua, Manuel Guzman, Silvia Gines
Summary: Increasing evidence suggests that activation of the unfolded protein response (UPR) due to accumulation of misfolded proteins in the endoplasmic reticulum (ER stress) is a key factor in neurodegenerative diseases. In Huntington's disease (HD), disruption of ER-associated degradation pathway and loss of ER protein homeostasis leads to neuronal dysfunction and degeneration. The PERK signaling pathway, in particular, has been found to contribute to memory disturbances and synaptic plasticity deficiencies in HD.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Multidisciplinary Sciences
Isabel Tundidor, Marta Seijo-Vila, Sandra Blasco-Benito, Maria Rubert-Hernandez, Sandra Adamez, Clara Andradas, Sara Manzano, Isabel Alvarez-Lopez, Cristina Sarasqueta, Maria Villa-Morales, Carmen Gonzalez-Lois, Esther Ramirez-Medina, Belen Almoguera, Antonio J. Sanchez-Lopez, Laura Bindila, Sigrid Hamann, Norbert Arnold, Christoph Roecken, Ignacio Heras-Murillo, David Sancho, Gema Moreno-Bueno, Maria M. Caffarel, Manuel Guzman, Cristina Sanchez, Eduardo Perez-Gomez
Summary: Clinical management of breast cancer metastasis is an unmet need. This study identifies fatty acid amide hydrolase (FAAH) as a predictor of prognosis in patients with luminal BC and a potential therapeutic target for preventing tumor progression and lung metastasis.
NATURE COMMUNICATIONS
(2023)
Review
Immunology
Iris Lodewijk, Marta Duenas, Jesus M. Paramio, Carolina Rubio
Summary: Targeted therapies are the latest technology in oncology, but finding suitable antigens or binders remains challenging. Specific cellular mechanisms provide a good source for new antigen expression. This article introduces several TAAs with potential for cancer monitoring, targeted therapy, and immunotherapy tools.
FRONTIERS IN IMMUNOLOGY
(2023)
Editorial Material
Endocrinology & Metabolism
Manuel Guzman
Summary: A study reveals that fatty acid oxidation in astrocytes can rearrange the respiratory chain to protect neuronal functionality and cognitive performance in mice.
Article
Neurosciences
Irene B. Maroto, Estefania Moreno, Carlos Costas-Insua, Javier Merino-Gracia, Rebeca Diez-Alarcia, Alicia Alvaro-Blazquez, Angeles Canales, Enric I. Canela, Vicent Casado, Leyre Uriguen, Ignacio Rodriguez-Crespo, Manuel Guzman
Summary: Cannabinoids have pleiotropic effects on the brain by interacting with the CB1 receptor. This study reveals that the interaction between CB1 receptor and GAP43 modulates CB1 receptor signaling in a highly selective manner, specifically impairing the ROCK signaling pathway and controlling neurite outgrowth.