{"title":"Haemostasis and the Need for Antithrombotics: An Introduction.","authors":"John Hogwood, Elaine Gray","doi":"10.1007/164_2026_796","DOIUrl":"10.1007/164_2026_796","url":null,"abstract":"<p><p>Antithrombotic and antiplatelet agents have been in use for over 100 years, with many listed as WHO essential medicines. Mortality and morbidity caused by cardiovascular diseases and due to arterial and venous thrombosis are increasing globally. The old legacy products such as heparin and warfarin, and the newer generation of agents, such as DOACs and anti-platelet agents, are needed to protect public health and reduce the burden on global healthcare systems. With new technologies and an increased understanding of the underlining mechanisms of thrombotic diseases, new drugs/therapies will continue to be developed. In addition, these therapies require monitoring to ensure safety and efficacy. This chapter sets the framework for this book.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147591766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structure-Bias Relationship of μ-Opioid Receptor Agonists.","authors":"Guodong He, Xiangyu Liu","doi":"10.1007/164_2025_772","DOIUrl":"10.1007/164_2025_772","url":null,"abstract":"<p><p>The μ-opioid receptor (μOR) is the primary drug target of opioid analgesics such as morphine and fentanyl. Activation of μORs in the central nervous system inhibits ascending pain signaling to the cortex, thereby producing analgesic effects. However, the clinical use of opioid analgesics is severely limited by adverse side effects, including respiratory depression, constipation, addiction, and the development of tolerance. μOR-mediated signaling involves both the G<sub>i/o/z</sub> protein pathway and the β-arrestin1/2 pathway. Recent research has indicated that G protein-biased agonists, which preferentially activate the G<sub>i/o/z</sub> pathway over the β-arrestin1/2 pathway, may provide effective analgesia with reduced side effects, thus offering improved therapeutic potential. In this chapter, we review the molecular basis of μOR-biased agonism. By integrating findings from structural and dynamic studies, we summarize the structure-bias relationships of various μOR agonists, aiming to provide valuable insights for the development of next-generation μOR-biased agonists.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"261-273"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structure-Encoded Location Biased Signaling in a Class B GPCR: Focus on the PTH Type 1 Receptor.","authors":"Karina A Peña, Jean-Pierre Vilardaga","doi":"10.1007/164_2025_763","DOIUrl":"10.1007/164_2025_763","url":null,"abstract":"<p><p>Research conducted over the last 15 years indicates that cAMP is generated not just from the plasma membrane but also from intracellular compartments, particularly in endosomes, where receptors are redistributed during the endocytosis process. This review centers on the parathyroid hormone type 1 receptor (PTH<sub>1</sub>R) as a model for a peptide hormone GPCRs that generates cAMP from various locations with distinct duration and pharmacological effectiveness. We discuss how structural dynamics simulations aid in designing ligands that induce cAMP location bias, ultimately answering how the spatiotemporal generation of cAMP affects pharmacological responses mediated by the PTH<sub>1</sub>R.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"65-85"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"KCTD Family: Emerging Regulators of GPCR Biased Signaling.","authors":"Wentong Jiang, Sanduo Zheng","doi":"10.1007/164_2025_766","DOIUrl":"10.1007/164_2025_766","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) engage multiple transducers to regulate distinct physiological processes. These transducers include various G proteins subtypes, GPCR kinases (GRKs), and β-arrestins. In addition to promoting receptor desensitization, β-arrestins serve as scaffolds for signaling via non-G protein pathways. Biased signaling enables GPCRs to selectively engage specific transducers, typically through different conformational states of GPCRs. While significant focus has been placed on developing biased ligands that preferentially activate specific G proteins or β-arrestins, the strategy focused on modulating particular G protein subunits (Gα versus βγ) remains underexplored. Recently, members of the KCTD (potassium channel tetramerization domain-containing) family have emerged as critical regulators of GPCR signaling, particularly through their roles in mediating Gβγ degradation or uncoupling Gβγ from downstream effectors. This ability positions the KCTD family as potential targets for selectively modulating Gβγ signaling with minimal impact on Gα-mediated pathways. In this chapter, we introduce the KCTD family, summarize current knowledge of their role in GPCR signaling regulation, and highlight unsolved questions in existing models, along with directions for future research.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"143-157"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Future Directions in GPCR Biased Signaling and Ligand Pharmacology.","authors":"Dannya Estau, Zijian Li","doi":"10.1007/164_2025_775","DOIUrl":"10.1007/164_2025_775","url":null,"abstract":"<p><p>G protein-coupled receptor (GPCR) biased signaling has emerged as a transformative paradigm, reshaping both fundamental understanding of receptor biology and pharmacological intervention. Significant advances have been made in deciphering the mechanisms underlying biased signaling and in the development of ligands that selectively engage specific pathways. Here, we outline key future directions in GPCR biased signaling and ligand pharmacology including the biased signaling theories, structural insights, methodological innovations and ligand pharmacology theories. We hope that these perspectives will contribute to pharmacological research, drug R & D, and clinical drug research and promoting safer and more effective GPCR-targeted treatments for human diseases.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"343-350"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Agonism and Biased Signaling.","authors":"Terry Kenakin","doi":"10.1007/164_2025_770","DOIUrl":"10.1007/164_2025_770","url":null,"abstract":"<p><p>This chapter considers biased signaling as a natural function of G protein-coupled receptors (GPCRs) in the form of probe dependence. Thus, any ligand that changes the conformation of the receptor (agonist, antagonist, or allosteric modulator) has the potential to change the natural signaling of the receptor through unequal conformational alterations in the receptor structure. This gives an added dimension to agonist selectivity beyond extracellular recognition, namely the ability of agonists to emphasize certain signaling pathways in the cell at the expense of others. Given this, selectivity is discussed in terms of varying intrinsic efficacy and selective stabilization of receptor states with methods to detect and measure these effects. Last, the translation of in vitro to complex in vivo systems will be considered.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"221-236"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jingzhi-Christina Zhou, Michelle Z Li, Alan Long, Alem W Kahsai
{"title":"Biased Allosteric Modulation in GPCR Drug Discovery.","authors":"Jingzhi-Christina Zhou, Michelle Z Li, Alan Long, Alem W Kahsai","doi":"10.1007/164_2025_771","DOIUrl":"10.1007/164_2025_771","url":null,"abstract":"<p><p>Allosteric modulation of G protein-coupled receptors (GPCRs) is emerging as a powerful approach in drug discovery, offering enhanced subtype selectivity and the ability to bias signaling toward therapeutically preferred pathways, thereby reducing off-target effects. While most approved GPCR drugs act via the orthosteric site, this approach often lacks subtype specificity and induces pleiotropic signaling that can compromise therapeutic efficacy. Orthosteric biased ligands have provided proof of concept for functional selectivity, yet their development has been limited by site homology and challenges in fine-tuning pathway specificity. In contrast, allosteric modulators (AMs) bind to spatially and structurally distinct, less conserved sites located across extracellular, transmembrane, and intracellular receptor domains. By stabilizing discrete receptor conformations, AMs can fine-tune transducer engagement and preferentially direct signaling toward either G protein or β-arrestin (βarr) pathway. Recent structural and biophysical studies have provided insights into how diverse AMs lock GPCRs in specific conformations and modulate signaling across receptor families. Taken together, these findings reflect a shift in GPCR pharmacology, driven by the convergence of biased signaling and allosteric modulation. Biased allosteric modulators (BAMs) represent a promising class of ligands that bind at allosteric sites and selectively tune signaling pathways by biasing orthosteric ligand-induced responses. This review outlines the principles of biased signaling and allosteric modulation and highlights strategies for designing BAMs for GPCRs. Identifying BAMs could revolutionize GPCR drug discovery by enabling pathway-specific precision therapeutics with improved efficacy and fewer side effects.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"237-259"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lorenzo Flori, Jacopo Spezzini, Eugenia Piragine, Valentina Citi, Vincenzo Calderone, Alma Martelli
{"title":"Naturally Occurring H<sub>2</sub>S-Donors in Vascular Diseases.","authors":"Lorenzo Flori, Jacopo Spezzini, Eugenia Piragine, Valentina Citi, Vincenzo Calderone, Alma Martelli","doi":"10.1007/164_2025_753","DOIUrl":"10.1007/164_2025_753","url":null,"abstract":"<p><p>Hydrogen sulfide (H<sub>2</sub>S) is an endogenous gasotransmitter able to exert a pivotal role in different organs and systems, strongly influencing cardiovascular health. It is an endowed antioxidant, a vasorelaxant, and has cardioprotective properties, thanks to the activation of different classes of potassium channels and the interaction with several pathways including those involving sirtuins, nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), and nitric oxide (NO) production. Alterations in the homeostasis of H<sub>2</sub>S represent an etiopathogenetic factor in the onset and progression of cardiovascular diseases, such as hypertension, atherosclerosis, and vascular diabetic complications, highlighting the therapeutic potential of exogeneous H<sub>2</sub>S-donors in H<sub>2</sub>S-poor diseases. Several natural H<sub>2</sub>S-donor compounds, or their precursors, derive from plants belonging to the Alliaceae (e.g., garlic and onion), Brassicaceae (e.g., broccoli and rocket salad), or Moringaceae (e.g., moringa) families. Preclinical studies demonstrated the antioxidant, vasoprotective, and anti-hypertensive properties of both plant extracts and isolated polysulfides or isothiocyanates (ITCs). In fact, polysulfides and ITCs are able to exert vascular effects superimposable to those induced by H<sub>2</sub>S. Preclinical and clinical studies successfully demonstrated that garlic extracts decrease systolic and diastolic blood pressure and contrast endothelial dysfunction and atherosclerosis. Similarly, preclinical studies highlighted the anti-inflammatory, anti-hypertensive, and vasoprotective properties of ITCs. However, clinical studies only demonstrated the improvement of the lipid profile in healthy patients, with no effects on systolic or diastolic blood pressure. Taken together, these findings suggest that natural H<sub>2</sub>S-donors could restore H<sub>2</sub>S homeostasis, therefore preventing and/or contrasting cardiovascular diseases.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"147-171"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Platelet Function Tests and Monitoring Antiplatelet Therapies.","authors":"Simon Davidson","doi":"10.1007/164_2025_788","DOIUrl":"10.1007/164_2025_788","url":null,"abstract":"<p><p>In the late 1990s, the antiplatelet agent clopidogrel, a P2Y12 inhibitor, was introduced into clinical practice. Concurrently, several new methods for assessing platelet function emerged, such as the PFA-100 in 1995, marking the beginning of a sustained expansion in platelet function testing. It soon became apparent that patient responses to clopidogrel varied significantly, with some individuals exhibiting high on-treatment platelet reactivity. This variability prompted discussions around the utility of platelet function testing to tailor antiplatelet therapy. Additionally, such testing was proposed for patients preparing for cardiac surgery to better manage the balance between thrombotic risk before surgery and bleeding risk during the perioperative period. This chapter explores widely used platelet function tests in these contexts, particularly those considered point-of-care (POC) or requiring minimal laboratory processing. It also reviews recent guidelines and clinical trial evidence, building on a previously published chapter, regarding the role and effectiveness of platelet function testing in these clinical scenarios.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"211-232"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li Lin, Yizhong Li, Shenglan Zhang, Cangsong Shen, Jiyong Meng, Jianfeng Liu
{"title":"GPCR Heterodimers: Implications for Biased Signaling.","authors":"Li Lin, Yizhong Li, Shenglan Zhang, Cangsong Shen, Jiyong Meng, Jianfeng Liu","doi":"10.1007/164_2025_762","DOIUrl":"10.1007/164_2025_762","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are key mediators of cellular signaling, participating in various physiological and pathological processes. Emerging evidence reveals that GPCRs can form functional heterodimers, wherein two distinct receptor subtypes interact mutually to generate unique signaling complexes. GPCR heterodimers play a crucial role in modulating cellular responses and are involved in biased signaling, a phenomenon where receptor activation preferentially triggers specific intracellular pathways (e.g., G protein vs. β-arrestin pathways). In this review, we will explore the molecular mechanisms underlying GPCR heterodimerization and the modulation of biased signaling in heterodimers. We first discuss the assembly and activation mechanisms based on heterodimerization in Class C GPCRs. Furthermore, we explore the impact of receptor dimerization on downstream biased signaling and the physiological relevance of these heterodimers. Next, we also summarize three criteria and essential technologies for identifying potential heterodimers. Lastly, we address the challenges and future directions in the study of GPCR heterodimers, particularly for drug discovery, highlighting their potential in designing novel therapeutics with enhanced specificity and reduced side effects.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"13-63"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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