Article
Multidisciplinary Sciences
Michelle D. Nemetchek, Ian M. Chrisman, Mariah L. Rayl, Andrew H. Voss, Travis S. Hughes
Summary: Efforts to decrease the adverse effects of nuclear receptor drugs have led to experimental agonists that produce better outcomes in mice. These agonists have been shown to cause different transcriptomic effects and a structural explanation for this remains unknown. The study reveals that partial agonists of the nuclear receptor peroxisome proliferator-associated receptor (PPAR) favor a different group of coactivator peptides compared to clinically used drugs, and differences in coactivator-PPAR bonding contribute to biased agonism. This provides a general structural mechanism for biased agonism in many nuclear receptors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Pharmacology & Pharmacy
Rafael Franco, Rafael Rivas-Santisteban, Irene Reyes-Resina, Gemma Navarro
Summary: Biased signaling refers to different signaling outputs depending on the chemical structure of the agonist, providing promise for new drug development strategies. This bias can be explained by the induced fit hypothesis and the key/lock hypothesis, and is influenced by the specific agonist.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Valeria Burghi, Emiliana B. Echeverria, Carlos D. Zappia, Antonela Diaz Nebreda, Sonia Ripoll, Natalia Gomez, Carina Shayo, Carlos A. Davio, Federico Monczor, Natalia C. Fernandez
Summary: Histamine H1 receptor ligands exhibit positive efficacy in receptor desensitization, internalization, signaling, and transcriptional regulation, showing a biased nature compared to reference agonists. These findings provide evidence for a more rational and safe use of histamine H1 receptor ligands.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Valeria Burghi, Emiliana B. Echeverria, Carlos D. Zappia, Antonela Diaz Nebreda, Sonia Ripoll, Natalia Gomez, Carina Shayo, Carlos A. Davio, Federico Monczor, Natalia C. Fernandez
Summary: Clinically used histamine H-1 receptor ligands exhibit biased efficacy in receptor desensitization and internalization, but lack efficacy in regulating COX-2 and IL-8 mRNA levels. Prolonged exposure to antihistamines impairs the increase in COX-2 and IL-8 mRNA levels induced by histamine, even after ligand removal. These findings provide evidence for a more rational and safe use of histamine H-1 receptor ligands.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Cell Biology
H. Ongun Onaran, Tommaso Costa
Summary: This review discusses the theoretical and experimental foundations for assessing agonism in GPCRs, emphasizing the importance of separating efficacy from affinity in understanding agonism and identifying ligands with true bias of efficacy for unraveling the conformational space that determines the complex functional chemistry of GPCRs.
CELLULAR SIGNALLING
(2021)
Review
Cell Biology
Qiwen Liao, Richard D. Ye
Summary: G protein-coupled chemoattractant receptors, such as FPR2, play a crucial role in leukocyte chemotaxis and have diverse cellular functions in response to various agonists. Recent studies have provided insights into the structural and conformational aspects of FPR2, revealing its ability to bind different ligands in different poses.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Zhenmei Xu, Tatsuya Ikuta, Kouki Kawakami, Ryoji Kise, Yu Qian, Ruixue Xia, Ming-Xia Sun, Anqi Zhang, Changyou Guo, Xue-Hui Cai, Zhiwei Huang, Asuka Inoue, Yuanzheng He
Summary: This study reveals that p-arrestin-biased ligands direct a distinct activation path in S1PR1 through extensive interplay between the PIF and the NPxxY motifs, with key features including the intermediate flipping of W269(6.48) and the retained interaction between F265(6.44) and N307(7.49). The structural insights provided in this study offer a rational basis for designing novel signaling-biased S1PR modulators.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Cell Biology
Krysten E. Ferraino, Natalie Cora, Celina M. Pollard, Anastasiya Sizova, Jennifer Maning, Anastasios Lymperopoulos
Summary: Angiotensin II (AngII) utilizes AT1R and AT2R G protein-coupled receptors to exert physiological effects, particularly impacting cardiovascular homeostasis. AT1R signaling mobilizes multiple signal transducers inside cells, with Gq/11 proteins and ?-arrestins specifically activated to promote aldosterone synthesis and secretion in the adrenal cortex. "Biased" signaling refers to preferential activation of one signaling pathway over others downstream of the same receptor, with therapeutic relevance in selectively promoting beneficial effects over detrimental consequences.
CELLULAR SIGNALLING
(2021)
Article
Multidisciplinary Sciences
Shi Liu, Zhen Yu, Eileen J. Daley, Craig A. Bingman, Austin T. Bruchs, Thomas J. Gardella, Samuel H. Gellman
Summary: In this study, the researchers discovered that modification of PTHR1 agonist at extracellular domain (ECD) contact sites can alter signaling profile, suggesting a modified two-step binding model. This model suggests that the orientation of the agonist on the ECD surface can influence the engagement between the agonist and the transmembrane domain (TMD) of the receptor.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Monica Patel, David B. Finlay, Michelle Glass
Summary: SCRAs were originally developed to explore therapeutic benefits of cannabinoid receptor activation, but have been diverted to the recreational drug market, potentially leading to toxicity. Biased agonists can maximize drug effectiveness by reducing adverse effects, but the signaling pathways of cannabinoid receptors are still unclear.
CELLULAR SIGNALLING
(2021)
Article
Multidisciplinary Sciences
Claire M. Grison, Paul Lambey, Sylvain Jeannot, Elise Del Nero, Simon Fontanel, Fanny Peysson, Joyce Heuninck, Remy Sounier, Thierry Durroux, Cedric Leyrat, Sebastien Granier, Cherine Bechara
Summary: The study reveals that leukotoxins HlgA and HlgB compete with endogenous chemokines by directly binding to the extracellular domain of ACKR1, impacting the structure and function of the receptor. Results show that toxin binding induces changes in the G protein-binding domain of ACKR1, leading to dissociation and alterations in the receptor's protein complexes within living cells.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Andrea Bedini, Elisabetta Cuna, Monica Baiula, Santi Spampinato
Summary: Chronic pain is a significant burden, and there is a need to develop more effective and safer analgesics. G protein-biased opioid agonists have been extensively studied as improved analgesic candidates, but the complex pharmacology of opioid receptors remains a challenge in translating them into improved therapeutics.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Endocrinology & Metabolism
Jiannan Xiao, Liliane El Eid, Teresa Buenaventura, Raphael Boutry, Amelie Bonnefond, Ben Jones, Guy A. Rutter, Philippe Froguel, Alejandra Tomas
Summary: This study aimed to determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon-like peptide-1 receptor (GLP-1R) balanced versus biased agonist stimulations. The results showed that acute and sustained GLP-1R agonist exposure had distinct effects on kinase responses, and different biased agonists could modulate distinct kinase interaction networks. These findings have important implications for the selection of appropriate anti-type 2 diabetes therapies.
DIABETES OBESITY & METABOLISM
(2023)
Article
Biochemistry & Molecular Biology
Agnes Acevedo-Canabal, Travis W. Grim, Cullen L. Schmid, Nina McFague, Edward L. Stahl, Nicole M. Kennedy, Thomas D. Bannister, Laura M. Bohn
Summary: Opioid analgesics such as morphine and fentanyl induce hyperactivity in mice through mu-opioid receptor (MOR). This study reveals that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy. Moreover, the intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay.
Review
Biochemistry & Molecular Biology
Krzysztof Jozwiak, Anita Plazinska
Summary: Studies on different receptors belonging to class A of GPCRs reveal specific molecular mechanisms behind ligand directed signaling, including the role of important residues, the impact of ligand structural features on signaling, and the key interactions between ligands and receptors.
Article
Cardiac & Cardiovascular Systems
Andrew B. Harvey, Renelyn A. Woltes, Raymond N. Deepe, Hannah G. Tarolli, Jenna R. Drummond, Allison Trouten, Auva Zandi, Jeremy L. Barth, Rupak Mukherjee, Martin J. Romeo, Silvia G. Vaena, Ge Tao, Robin Muise-Helmericks, Paula S. Ramos, Russell A. Norris, Andy Wessels
Summary: This study highlights the importance of SOX9 in the regulation of epicardial cell invasion and emphasizes the role of EPDCs in regulating atrioventricular valve development and homeostasis. It also reports a novel expression profile of Cd109, a gene with previously unknown relevance in heart development.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2024)
Review
Cardiac & Cardiovascular Systems
MariaSanta C. Mangione, Jinhua Wen, Dian J. Cao
Summary: mTOR, a mechanistic target of rapamycin, is an evolutionarily conserved pathway that plays a fundamental role in nutrient sensing, growth, metabolism, lifespan, and aging. Recent studies have highlighted the regulatory role of mTOR in innate immune responses and its involvement in the pathogenesis of cardiovascular diseases, especially in acute inflammation and atherosclerotic cardiovascular disease. This review also discusses mTOR's role in trained immunity, immune senescence, and clonal hematopoiesis, as well as its architecture and regulatory complexes.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2024)
Article
Cardiac & Cardiovascular Systems
Junlin Li, Yajun Gong, Yiren Wang, Huihui Huang, Huan Du, Lianying Cheng, Cui Ma, Yongxiang Cai, Hukui Han, Jianhong Tao, Gang Li, Panke Cheng
Summary: Myocardial ischemia-reperfusion injury is closely related to the final infarct size in acute myocardial infarction. Regulatory T cells play an important role in the inflammatory response after AMI, but different subtypes of Tregs have different effects on the injury.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2024)
Article
Cardiac & Cardiovascular Systems
Yuxin Chu, Yutao Hua, Lihao He, Jin He, Yunxi Chen, Jing Yang, Ismail Mahmoud, Fanfang Zeng, Xiaochang Zeng, Gloria A. Benavides, Victor M. Darley-Usmar, Martin E. Young, Scott W. Ballinger, Sumanth D. Prabhu, Cheng Zhang, Min Xie
Summary: This study demonstrates that administering beta-hydroxybutyrate (beta-OHB) at the time of reperfusion can reduce infarct size and preserve cardiac function by activating autophagy and preserving mitochondrial homeostasis, potentially through mTOR inhibition.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2024)