Handbook of experimental pharmacology最新文献_第9页

Biased Allosteric Modulation in GPCR Drug Discovery. GPCR药物发现中的偏置变构调节。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_771

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":"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.","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}

引用次数: 0

GPCR Heterodimers: Implications for Biased Signaling. GPCR异源二聚体：对偏置信号的影响。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_762

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":"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.","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}

引用次数: 0

The Role of Hydrogen Sulfide in Peripheral Nervous System Modulation. 硫化氢在周围神经系统调节中的作用。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_777

Saúl Huerta de la Cruz, Diana L Silva-Velasco, Jesus H Beltran-Ornelas, David Centurión

{"title":"The Role of Hydrogen Sulfide in Peripheral Nervous System Modulation.","authors":"Saúl Huerta de la Cruz, Diana L Silva-Velasco, Jesus H Beltran-Ornelas, David Centurión","doi":"10.1007/164_2025_777","DOIUrl":"10.1007/164_2025_777","url":null,"abstract":"Hydrogen sulfide (H2S) is a gasotransmitter that contributes to the regulation of peripheral nervous system (PNS) function. H2S is produced by several enzymes whose expression changes under different physiological and pathological conditions, influencing how peripheral neurons respond to environmental and internal signals. H2S modulates neuronal excitability through its actions on ion channels and through interactions with other gasotransmitters, shaping sensory, autonomic, and pain-related pathways. In autonomic circuits, H2S adjusts sympathetic and parasympathetic activity. Through these actions, it affects cardiovascular control, gastrointestinal motility, and respiratory rhythm. In pain pathways, H2S can modulate nociception in either direction, with its effectsshaped by the physiological or pathological state. H2S participates in multiple pain conditions and contributes to changes in peripheral and spinal processing that influence pain sensitivity. Overall, H2S influences several components of peripheral neurobiology and represents a potential target for strategies aimed at treating autonomic dysfunction and chronic pain.","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"41-64"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762677","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}

引用次数: 0

Biased Agonism at β-Adrenoceptor Subtypes: A Drug Development Perspective. β-肾上腺素能受体亚型的偏向激动作用：药物开发的观点。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_769

Martin C Michel, Ongun Onaran

{"title":"Biased Agonism at β-Adrenoceptor Subtypes: A Drug Development Perspective.","authors":"Martin C Michel, Ongun Onaran","doi":"10.1007/164_2025_769","DOIUrl":"10.1007/164_2025_769","url":null,"abstract":"Selectivity of a drug for a desired response as compared to undesirable responses (side effect) is a key goal of drug development. Early concepts to achieve such selectivity were based on selectivity for a molecular target as compared to others, pharmacokinetic factors to achieve high concentrations in the target tissue as compared to low concentrations in others, differential efficacy in the target vs. others tissues, and leveraging the concept of cell type and tissue differences in expression levels of receptors and their related signaling molecules, which can be further complicated by alterations of such ratios in disease. Biased agonism occurs when one response is activated preferentially over another after accounting for the above other factors. Thus, assessment of ligand bias is not always easy. β-Adrenoceptors have played a relevant role in our understanding of the phenomenon of biased agonism. Several clinically used β-adrenoceptor ligands were proposed to exhibit biased agonism, but the findings often are inconclusive, at least partly based on the overall complexity of assessment of biased signaling. These complexities also make it challenging to determine the desired biased profile of a ligand at the start of a drug research and development project, particularly for innovative applications. Thus, biased agonism has potential to contribute to functional target selectivity, but its prospective use remains challenging.","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"203-219"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058235","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}

引用次数: 0

H₂S Signaling and SKM Physiopathology. H2S信号和SKM生理病理。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_779

Valentina Vellecco, Martina Smimmo, Veronica Casale, Mariarosaria Bucci

引用次数: 0

The SERCA Pump: A Key Molecular Target in Calcium Handling of Vascular Smooth Muscle Cells in Metabolic Syndrome. SERCA泵：代谢综合征血管平滑肌细胞钙处理的关键分子靶点。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2026_798

Cristian J Arriero-Carrillo, Angélica Rueda

{"title":"The SERCA Pump: A Key Molecular Target in Calcium Handling of Vascular Smooth Muscle Cells in Metabolic Syndrome.","authors":"Cristian J Arriero-Carrillo, Angélica Rueda","doi":"10.1007/164_2026_798","DOIUrl":"10.1007/164_2026_798","url":null,"abstract":"The calcium ion (Ca2+) is a fundamental intracellular messenger involved in the transduction of diverse receptor signaling pathways. Transient increases in cytoplasmic Ca2+ concentration ([Ca2+]cyt) regulate many cellular functions, including the contraction of vascular smooth muscle cells (VSMCs), which are active components of the blood vessels. A key protein in intracellular Ca2+ handling is the sarco/endoplasmic reticulum (SR/ER) Ca2+ ATPase, or SERCA pump. This transmembrane protein belongs to the P-type ATPase family and uses energy from ATP hydrolysis to transport Ca2+ from the cytoplasm into intracellular reservoirs within the SR of VSMCs. By lowering [Ca2+]cyt, SERCA activity promotes vasorelaxation. In mammals, three genes, ATP2A1, ATP2A2, and ATP2A3, encode at least twelve SERCA pump isoforms. Alternative mRNA splicing is the primary mechanism for generating most isoforms, leading to tissue-specific expression patterns. In VSMCs from the aorta and mesenteric arteries, the expression of SERCA2a, SERCA2b, and, more recently, SERCA3 has been reported. This chapter will review the structure, mechanism of action, and physiological role of the SERCA pump in the intracellular Ca2+ handling of VSMCs, as well as its alterations in metabolic syndrome.","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"105-126"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147868084","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}

引用次数: 0

Experimental Models for Studying Cardiovascular Dysfunction in Metabolic Syndrome. 代谢综合征心血管功能障碍研究的实验模型。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2026_800

Jade L Taylor, Eric A Pereira da Silva, Hannah M Voorhees, Maryann K Ferrara, Sophia Salbato, Nuria Daghbouche-Rubio, Miguel Martín-Aragón Baudel, Madeline Nieves-Cintrón

引用次数: 0

GPCR Biased Signaling in Cancer. 肿瘤中GPCR偏倚信号传导。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_773

Ariella C Avigad, Melody Zhou, Chengyu Sun, Levin Ma, Xue Li, Rosie J Blodgett, Vera S Donnenberg, Albert D Donnenberg, Patrick L Wagner, David L Bartlett, Kunhong Xiao

{"title":"GPCR Biased Signaling in Cancer.","authors":"Ariella C Avigad, Melody Zhou, Chengyu Sun, Levin Ma, Xue Li, Rosie J Blodgett, Vera S Donnenberg, Albert D Donnenberg, Patrick L Wagner, David L Bartlett, Kunhong Xiao","doi":"10.1007/164_2025_773","DOIUrl":"10.1007/164_2025_773","url":null,"abstract":"G protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors. They orchestrate various signaling pathways, playing a central role in regulating various physiological and pathophysiological processes. Dysregulation of GPCR signaling has been intricately linked to cancer pathogenesis, including tumor growth, angiogenesis, metastasis, and immune modulation. Biased GPCR signaling occurs when a ligand preferentially activates one signaling pathway over another, leading to distinct cellular outcomes. In cancer, biased GPCR signaling represents a complex, dynamic phenomenon, significantly influencing cancer development, progression, and treatment resistance. This chapter reviews recent advances in our understanding of GPCR biased signaling in various aspects of cancer biology and explores its therapeutic potential. Given the fragmented nature of existing evidence, we integrate available literature with findings from our own proteomics studies on GPCR and β-arrestin function to provide a preliminary framework for understanding β-arrestin-mediated signaling in cancer. While this overview may capture only a limited snapshot of the broader landscape, it provides a valuable foundation for generating new hypotheses and guiding future research and drug discovery efforts in oncology.","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"277-318"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400651","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}

引用次数: 0

Sexual Dimorphism in the Development of Cardiometabolic Syndrome. 两性异形在心脏代谢综合征发展中的作用。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2026_790

Myrian Velasco, Alondra Albarado-Ibañez, Carlos Larqué, Pablo Pánico, Julián Torres-Jacome, Marcia Hiriart

引用次数: 0

Antiplatelet Therapy. 抗血小板治疗。

Handbook of experimental pharmacology Pub Date : 2026-01-01 DOI: 10.1007/164_2025_784

Richard T Amison, Simon C Pitchford

引用次数: 0