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":"https://doi.org/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":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-08","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}
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":"https://doi.org/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":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-08","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}
{"title":"Agonism and Biased Signaling.","authors":"Terry Kenakin","doi":"10.1007/164_2025_770","DOIUrl":"https://doi.org/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":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-04","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}
{"title":"Structural Perspectives on Biased Allostery of GPCR Signaling.","authors":"Chang Zhao, Siyuan Shen, Chao Wu, Renxuan Luo, Wei Yan, Zhenhua Shao","doi":"10.1007/164_2025_767","DOIUrl":"https://doi.org/10.1007/164_2025_767","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are highly dynamic membrane receptors with numerous subtypes and complex signal transduction pathways. Precise regulation of GPCR signaling is closely related to disease treatment but presents significant challenges with classical orthosteric ligands. Allosteric modulators, a class of emerging drug candidates, can selectively bind to the allosteric sites located outside the conserved orthosteric pocket. In particular, biased allosteric modulators (BAMs) can stabilize specific conformations of GPCRs to harness signal transduction with high selectivity and specificity, offering a novel approach to modulate GPCR pharmacology and develop safer therapeutic agents. In recent years, significant progress has been made in the study of GPCR allosteric modulation due to advancements in structural biology. However, knowledge about GPCR-biased allostery is still in its infancy. In this chapter, we present the most recent breakthroughs in the discovery of BAM binding site in GPCRs and provide structural insights into biased allostery of GPCR signaling.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199101","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":"Structural Basis of GPCR-Biased Modulation.","authors":"Yan Zhang","doi":"10.1007/164_2025_768","DOIUrl":"https://doi.org/10.1007/164_2025_768","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) constitute the largest superfamily of membrane receptors in humans and serve as crucial targets for drug development. These receptors engage multiple downstream signaling pathways, including various G-proteins and arrestins, each of which can elicit distinct physiological and pathological responses. Understanding the mechanisms of biased signaling among these pathways is vital for designing more effective drugs with reduced side effects. In this chapter, we summarize the current understanding of how GPCRs selectively couple to different signaling proteins. We delve into the structural insights derived from recent studies, which reveal how ligands can stabilize specific receptor conformations, thereby favoring particular signaling pathways over others. Furthermore, we highlight various biased ligands and their mechanisms of action, emphasizing their therapeutic potential. These findings provide a critical structural foundation for future drug discovery and optimization efforts, paving the way for more targeted and safer pharmacological interventions. Through a deeper comprehension of biased signaling mechanisms, we aim to enhance the efficacy and safety profiles of new therapeutic agents.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199133","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}
Mingda Chen, Zachary W Grimmett, Richard T Premont, Jonathan S Stamler
{"title":"S-Nitrosylation of GPCR Regulatory Machinery as a Mechanism to Bias Signaling.","authors":"Mingda Chen, Zachary W Grimmett, Richard T Premont, Jonathan S Stamler","doi":"10.1007/164_2025_765","DOIUrl":"https://doi.org/10.1007/164_2025_765","url":null,"abstract":"<p><p>Upon stimulation by endogenous ligands, G protein-coupled receptors (GPCRs) activate downstream signaling pathways through multiple mechanisms, including G protein subtypes, β-arrestins, and receptor-specific partners. Synthetic ligands may activate only a subset of these pathways, resulting in functional selectivity or signaling bias. Since not all signaling outputs are therapeutically desirable, there is pharmaceutical interest in exploiting biased signaling. Although much effort is focused on designing ligands to induce receptor conformations that result in signal bias, it is also true that cellular systems adapt dynamically in ways that tune receptor signaling, termed system bias. In this chapter, we provide evidence that posttranslational modification of receptor machinery by S-nitrosylation is an important regulator of system bias in GPCR signaling. S-nitrosylation has been reported to affect the function of multiple classes of GPCR signaling pathway components, including receptors, G proteins, G protein-coupled receptor kinases, β-arrestins, and others. Further, untargeted proteomic studies of S-nitrosylated proteins have identified over 60 GPCRs, most heterotrimeric G proteins, and numerous GPCR signaling components, hinting at a class effect and unifying mechanism to bias the functional repertoires of GPCRs in vivo. Thus, protein S-nitrosylation provides prototypic examples for how post-translational regulatory mechanisms bias GPCRs endogenously.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199152","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":"GPCR Phospho-Barcodes and Biased Signaling.","authors":"Qingtao He, Jinpeng Sun, Shenming Huang","doi":"10.1007/164_2025_761","DOIUrl":"https://doi.org/10.1007/164_2025_761","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs), the largest family of membrane receptors in humans, primarily regulate diverse physiological and pathological processes through G protein- and arrestin-mediated signaling pathways, making them important drug targets. Notably, arrestins not only mediate GPCR desensitization and internalization but also regulate G protein-independent signal transduction. However, the mechanisms underlying arrestin-mediated biased signaling remain incompletely understood, posing significant challenges for developing targeted GPCR drugs with signaling bias. To address this knowledge gap, researchers have conducted systematic investigations and proposed innovative models, including the flute model, the polyproline sorting dock model, and the time order effects of GPCR phospho-barcodes to elucidate the dynamic processes driving biased signaling in arrestin activations. These key findings not only refine the theoretical framework of GPCR phosphorylation in biased signaling but also provide a solid foundation for developing biased drugs targeting the GPCR-arrestin pathway, offering new opportunities for precision therapeutics in diverse diseases.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185460","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":"https://doi.org/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":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-14","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}
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":"https://doi.org/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":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-14","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}
{"title":"GPCR Biased Signaling in Metabolism.","authors":"Zhaoyu Zhang, Zijian Li","doi":"10.1007/164_2025_774","DOIUrl":"https://doi.org/10.1007/164_2025_774","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and the most prominent drug targets. GPCR-biased signaling exerts different functions through distinct downstream signaling pathways of receptor to maintain body homeostasis. Metabolism is the series of biochemical processes that occur within a living organism to maintain life. GPCR-biased signaling and metabolism exhibit bidirectional interplay. On the one hand, metabolites including short-chain fatty acids (SCFAs) and long-chain fatty acids (LCFAs) act as ligands inducing biased GPCRs signaling. On the other hand, activated GPCRs regulate diverse metabolic functions by biased signal sorting (G protein or β-arrestin-mediated). G protein signaling mainly mediates rapid metabolic reaction, and β-arrestin signaling mainly mediates sustained metabolic effects. In clinical drug applications, GPCR-biased drugs can revolutionize metabolic disease therapeutics by enabling pathway-selective drug design to enhance efficacy while reducing side effects. Thus, delving deeper into the relationship between GPCR-biased signaling and metabolism is of great importance in physiology, pathology, and pharmacology. A systematic exploration of biased signaling will enhance insights into GPCRs-metabolism interactions, aiding disease mechanism studies, drug discovery, and clinical treatment strategies.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058262","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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