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
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.
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
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
Endocrinology & Metabolism
Valentine Suteau, Valerie Seegers, Mathilde Munier, Rym Ben Boubaker, Cecile Reyes, David Gentien, Meline Wery, Anne Croue, Frederic Illouz, Antoine Hamy, Patrice Rodien, Claire Briet
Summary: This study analyzed the GPCR expression in progressive and refractory thyroid cancers, identifying potential targets for drug repositioning. Several downregulated or deregulated GPCRs were found in thyroid tumors, providing opportunities for precision medicine in radioiodine-refractory thyroid cancer.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2021)
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.
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)
Review
Endocrinology & Metabolism
Siyuan Shen, Chang Zhao, Chao Wu, Suyue Sun, Ziyan Li, Wei Yan, Zhenhua Shao
Summary: GPCRs, as the largest family of transmembrane proteins, regulate various physiological processes. However, their complicated signal transduction pathways and difficulties in drug development have presented challenges. By identifying new ligands that bind to allosteric sites, safer drugs for treating various diseases can be designed.
FRONTIERS IN ENDOCRINOLOGY
(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
Biochemistry & Molecular Biology
Carolina Villarroya-Beltri, Ana Filipa B. Martins, Alejandro Garcia, Daniel Gimenez, Eduardo Zarzuela, Monica Novo, Cristina Del Alamo, Jose Gonzalez-Martinez, Gloria C. Bonel-Perez, Irene Diaz, Maria Guillamot, Massimo Chiesa, Ana Losada, Osvaldo Grana-Castro, Meritxell Rovira, Javier Munoz, Maria Salazar-Roa, Marcos Malumbres
Summary: Maintenance of stemness is regulated by CDC14, a CDK-counteracting phosphatase, which dephosphorylates UTF1 to trigger its degradation and control neural differentiation. Lack of CDC14 results in deficient neural system development and impaired neural differentiation from ESCs. CDC14 phosphatases are critical molecular switches linking cell cycle regulation and self-renewal.
Article
Chemistry, Physical
Nathalia Freitas Freire, Paulo Emilio Feuser, Elena Maria Tovar Ambel, Marco Cordani, Ellen De Pieri, Ricardo Andrez Machado-de-Avila, Acacio A. F. Zielinski, Claudia Sayer, Pedro Henrique Hermes de Araujo, Guillermo Velasco Diez, Elaine Cabral Albuquerque, Rosana Lopes Lima Fialho
Summary: THC, CBD, and other natural compounds produced by Cannabis sativa have therapeutic effects on the human body. Full spectrum extracts, containing controlled amounts of different cannabinoids, are being studied for their potential use in treating diseases like cancer. However, cannabinoids have limited bioavailability due to their low solubility in water and moderate stability. Therefore, there is a need to develop novel methods of cannabinoid administration or encapsulation to improve their efficacy.
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
(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)
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
Oncology
Nuria G. Martinez-Illescas, Silvia Leal, Patricia Gonzalez, Osvaldo Grana-Castro, Juan Jose Munoz-Oliveira, Alfonso Cortes-Pena, Maria Gomez-Gil, Zaira Vega, Veronica Neva, Andrea Romero, Miguel Quintela-Fandino, Eva Ciruelos, Consuelo Sanz, Sofia Aragon, Leisy Sotolongo, Sara Jimenez, Eduardo Caleiras, Francisca Mulero, Cristina Sanchez, Marcos Malumbres, Maria Salazar-Roa
Summary: A hallmark of many malignant tumors is the presence of dedifferentiated cells that have lost their resemblance to normal cells. These dedifferentiated cells have a higher survival capacity and can incite tumor relapse. Differentiation therapy that induces cancer cell differentiation could be combined with current standard care to treat aggressive tumors. MicroRNA 203 has been shown to promote the differentiation of breast cancer cells, preventing tumor growth in vivo. This research sheds light on differentiation-based antitumor therapies and highlights the potential of miR-203 as a tool to directly combat tumor maintaining and regeneration capabilities.
BREAST CANCER RESEARCH
(2023)
Article
Oncology
Esther Cabanas Morafraile, Cristina Saiz-Ladera, Cristina Nieto-Jimenez, Balazs Gyorffy, Adam Nagy, Guillermo Velasco, Pedro Perez-Segura, Alberto Ocana
Summary: This study describes a novel therapeutic strategy for treating colorectal cancer (CRC) patients with BRAF mutations. By identifying upregulated proteins on the surface of tumor cells as treatment targets and observing the transcriptional profile associated with antigen presenting cells, it is suggested that a combination of anti PD(L)1 with other co-inhibitor receptors can be explored for treating BRAF-mutated CRC patients.
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.
