Handbook of experimental pharmacology最新文献

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.

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.

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.

GPCRs are known for their versatile signaling roles at the plasma membrane; however, recent studies have revealed that these receptors also function within various intracellular compartments, such as endosomes, the Golgi apparatus, and the endoplasmic reticulum. This spatially distinct signaling, termed location bias, allows GPCRs to initiate unique signaling cascades and influence cellular processes-including cAMP production, calcium mobilization, and protein phosphorylation-in a compartment-specific manner. By mapping the impact of GPCR signaling from these subcellular locations, this chapter emphasizes the mechanisms underlying signaling from intracellular receptor pools in diversifying receptor functionality. Such mechanistic insights into location-biased signaling open up novel therapeutic strategies aimed at targeting GPCRs within specific organelles, promising new levels of precision in therapeutic modulation and potential improvements in treatment efficacy and specificity.

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.

Platelets are central mediators of haemostasis, responding rapidly to vascular injury through tightly regulated activation and inhibitory mechanisms. This response is mediated by a range of agonists, membrane receptors, and associated signalling pathways, enabling platelets to respond rapidly and specifically to stimuli. This chapter outlines the processes of platelet activation following vascular damage, highlighting the roles of collagen, von Willebrand factor, and secondary agonists such as ADP, thromboxane A₂, and thrombin, alongside endothelial-derived inhibitory signals that restrain excessive activation. It focuses on tyrosine kinase-linked receptors, detailing immunoreceptor tyrosine-based activatory (ITAM and hemITAM) and inhibitory (ITIM/ITSM) pathways, with emphasis on key kinases including Src family kinases, Syk, and Tec family members, and receptors such as GPVI, FcγRIIA, CLEC-2, PECAM-1, and G6b-B. Adhesion receptors, particularly integrins αIIbβ3 and α2β1 and the GPIb- IX-V complex, are examined with respect to inside-out and outside-in signalling and mechanotransduction. Finally, the G-protein-coupled receptors that amplify or inhibit platelet responses are discussed, including PARs, purinergic receptors, thromboxane, and prostaglandin receptors, along with emerging concepts in the regulation of platelets by GPCRs and in therapeutic targeting. The activatory and inhibitory pathways outlined here work together to maintain a balance between haemostasis and thrombosis. This enables a rapid and coordinated platelet response to vascular damage while preventing inappropriate and excessive activation. This maintains vascular integrity while preventing excessive bleeding and pathological thrombosis.

Hydrogen sulfide (H₂S) is an important gasotransmitter with multiple roles and is involved in several pathophysiological processes, including atherosclerosis and associated cardiometabolic comorbidities. This chapter examines the molecular mechanisms by which H₂S can influence the development and progression of atherosclerosis, including its effects on vascular tone, angiogenesis, oxidative stress, and inflammation, which can also affect atherosclerotic plaque stability. Moreover, we describe how H₂S affects the outcomes of cardiometabolic comorbidities associated with atherosclerosis, such as diabetes, hypertension, cardiac ischemia-reperfusion injury (IRI), stroke, metabolic-associated fatty liver disease (MAFLD), and kidney disease. Finally, we discuss how H₂S levels could potentially serve as biomarkers and the potential of increasing H₂S levels (both donors and metabolic pathway modulators) as promising therapeutic agents for improving vascular function, reducing plaque formation, and mitigating cardiovascular disease risk.

This chapter provides a comprehensive overview of direct oral anticoagulants (DOACs), focusing on their mechanisms of action, clinical utility, and practical considerations in anticoagulation management. DOACs have revolutionised anticoagulation by selectively targeting thrombin and activated factor X (FXa), offering improved safety, predictable pharmacokinetics, and reduced need for monitoring. The chapter covers their indications, contraindications, dosing, perioperative management, reversal, and use in special populations, including those with renal or hepatic impairment, cancer-associated thrombosis, and extreme body weights. It provides clinicians with practical guidance for the effective application of DOACs in various clinical settings.

This chapter provides an overview of heparin, including discovery, structure, mechanism of action, and principal use for anticoagulation. For over 100 years, heparin has a central role in prophylaxis and treatment of prothrombotic states, be it used in the event of pulmonary embolism or maintaining blood fluidity during dialysis. Indeed, heparin had a role in enabling the development of cardiopulmonary bypass for the surgical treatment of cardiopulmonary diseases. The development of heparin depolymerization which produced low molecular weight heparin further enhanced the usefulness of this anticoagulant, where this type of heparin can be self-administered. There has been much written about heparin over the last century, and this chapter provides a concise overview.

Hydrogen sulfide (H₂S) is increasingly recognized as gaseous endogenous molecule for its significant role in various physiological processes, behind its historical association with toxicity. Recent studies have highlighted H₂S's cytoprotective properties, including antioxidant, anti-inflammatory, and antifibrotic effects, particularly in the context of skeletal muscle (SKM) health. SKM disorders, such as muscular dystrophy, human malignant hyperthermia, and sarcopenia, lead to severe structural and functional impairments that adversely affect the quality of life. Although limited literature is available on the role of H₂S in SKM physiopathology, it is gaining special interest. Emerging evidence suggests that H₂S may have a protective role in mitigating muscle damage and dysfunction. This chapter explores the dual functions of H₂S in SKM physiology and pathophysiology, emphasizing its potential therapeutic applications. We propose that H₂S-based strategies may offer promising avenues for alleviating the progression of muscle-related disorders and warrant further investigation to fully elucidate its mechanisms of action.