Receptors, Volume 5, Issue 2 (June 2026) – 12 articles

The dopamine D₃ receptor (D₃R) has long been considered a secondary target in the treatment of Parkinson’s disease (PD), with therapeutic strategies primarily focused on D₂ receptor–mediated motor control. However, accumulating evidence now supports D₃R as a functionally distinct dopaminergic receptor subtype with specific relevance to non-motor symptom domains and dopaminergic signaling under hypodopaminergic conditions. Recent advances in high-resolution structural biology have elucidated the molecular basis of D₃R/D₂R discrimination, revealing how subtle residue-level and microstructural differences within a conserved G protein–coupled receptor framework shape ligand recognition and receptor activation. In parallel, the emergence of ligand-dependent biased signaling has refined current understanding of D₃R pharmacology. Selected ligands can preferentially engage Gα_i/o-mediated pathways while limiting β-arrestin recruitment and associated regulatory processes, providing a mechanistic rationale for more stable modulation of mesolimbic dopaminergic circuits involved in affective and motivational regulation. Beyond symptomatic modulation, preclinical studies suggest that D₃R signaling may influence neuronal resilience, synaptic plasticity, and adaptive responses to dopaminergic injury; however, such effects remain experimental and have not been demonstrated in clinical PD. This review integrates recent structural, signaling, and functional insights into D₃R biology, with particular emphasis on biased agonism and emerging therapeutic concepts. Although D₃R-targeted strategies do not currently represent disease-modifying interventions, they offer a rational framework for the development of next-generation dopaminergic therapies aimed at improving precision, tolerability, and long-term signaling stability in Parkinson’s disease. Full article

Olfactory (or odorant) receptors (ORs) were initially characterized in 1991 by Drs. Richard Axel and Linda Buck, and subsequent additional efforts have contributed to our understanding of their canonical function in odorant identification in the nasal cavity, including ligands for many of the ORs and the signaling pathways involved. More recently, OR transcripts and proteins have been identified in cells and organs outside of the nasal cavity, ranging from skin to sperm to tumors, suggesting that they have biological roles in ectopic locations other than their canonical function of odorant molecule detection in the nose. This mini narrative review discusses ectopic human ORs and their potential ligand-activated functions in the skin, lung, and sperm, as well as in diseases such as nonalcoholic steatohepatitis (NASH), melanoma and prostate cancer. Full article

The mechanosensitive PIEZO family channels, PIEZO1 and PIEZO2, are essential for mechanotransduction and play roles in many cellular processes, including cell volume regulation, tissue development, touch sensation, and proprioception. Emerging evidence suggests roles for PIEZO channels in cancer biology; however, direct mechanistic evidence in breast cancer remains limited. They have been shown to promote proliferation, epithelial-to-mesenchymal transition (EMT), and migration; however, these roles are varied and context-dependent. In breast cancer specifically, the two PIEZO channels may play opposing and complex roles in tumor progression, the tumor microenvironment (TME), and the tumor immune microenvironment (TIME), potentially impacting therapeutic response and prognosis. Where breast cancer-specific mechanistic data are lacking, we integrate findings from other tumor types to generate testable hypotheses relevant to breast cancer. In this review, we will explore the importance of PIEZO channels in breast cancer development, progression, and therapeutic response, and explore therapeutics and potential strategies to improve patient outcomes. Full article

Immune checkpoint receptors (ICRs) play a pivotal role in modulating antitumor immunity and have become central targets in the immunotherapy of genitourinary (GU) malignancies. This review provides a comprehensive overview of the fundamental mechanisms of ICR signaling, the expression and pathophysiological roles of these receptors in GU cancers (kidney, bladder, prostate, testicular, and penile), and the evolving therapeutic landscape. Key ICRs, including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT, orchestrate complex signaling cascades that can lead to T-cell exhaustion and tumor immune evasion. Their expression varies significantly across GU cancer types, histological subtypes, and tumor stages, influencing prognosis and therapeutic response. Immune checkpoint inhibitors (ICIs) reinvigorate antitumor immunity by disrupting these inhibitory pathways and remodeling the tumor microenvironment (TME); however, resistance mechanisms (primary, adaptive, and acquired) and immune-related adverse events (irAEs) pose significant clinical challenges. Established biomarkers such as PD-L1 expression, tumor mutational burden (TMB), and microsatellite instability (MSI)/deficient mismatch repair (dMMR) status guide ICI use, but their predictive power has limitations. Consequently, emerging tissue-based (e.g., immune cell signatures, multiplex IHC/IF, spatial transcriptomics), liquid biopsy-based (e.g., ctDNA, CTCs, exosomes), and imaging-based (radiomics, AI-driven analysis) biomarkers are under active investigation to refine patient selection and monitor treatment efficacy. The therapeutic armamentarium is rapidly expanding with novel ICIs targeting new receptors, bispecific antibodies, and innovative combination strategies involving ICIs with chemotherapy, targeted therapies, radiotherapy, and other immunotherapies. Furthermore, ICIs are increasingly explored in neoadjuvant, adjuvant, and maintenance settings. This review highlights the dynamic progress in understanding ICR biology and its clinical translation, emphasizing the ongoing efforts to develop more personalized and effective immunotherapeutic strategies for patients with genitourinary tumors. Full article

Background: The World Health Organization (WHO) declared a pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiologic agent responsible for Coronavirus Disease 2019 (COVID-19). Although case numbers declined after the initial outbreak, Brazil experienced slight increases in COVID-19 cases in 2024 and 2025, underscoring the persistent need for effective therapeutic interventions. Recently, proxalutamide—an androgen receptor antagonist—has been proposed as a potential therapeutic agent against COVID-19, as supported by several clinical studies. Methods: In the present work, we aimed to elucidate the molecular interactions between proxalutamide and key proteins involved in the viral fusion and replication processes of SARS-CoV-2. Computational techniques, including molecular docking and molecular dynamics simulations, were employed. Results: Our analyses indicated a high success rate, with stable conformations and favorable binding affinity values for ACE2 (−8.90 kcal/mol) and TMPRSS2 (−9.28 kcal/mol), resulting in strong docking scores. Moreover, molecular dynamics simulations confirmed the stability of these complexes, as evidenced by consistent mean square deviation values, low structural flexibility, a stable radius of gyration, and maintained surface rigidity over a 100 ns simulation period. Conclusions: These combined docking and dynamics results suggest that proxalutamide interacts firmly with the active sites, indicating high binding affinity that may interfere with SARS-CoV-2 entry. Nevertheless, experimental validation and rigorous safety assessments are warranted to confirm this potential. Full article

Interleukin-17A (IL-17A) is a proinflammatory cytokine that plays a pivotal role in immune responses and tissue homeostasis. Its expression is strictly regulated by transcription factors including RORγt, and it is mainly produced by Th17 cells, γδ T cells, and innate lymphoid cells. IL-17A signals through a heterodimeric receptor complex consisting of IL-17RA and IL-17RC, activating NF-κB, MAPK, and C/EBP pathways via the adaptor protein Act1. IL-17 signaling is counterbalanced by negative regulators including A20 and Regnase-1. Beyond its classical roles in antimicrobial defense and autoimmune inflammation, recent studies have highlighted its functions in the central nervous system, with associations to multiple sclerosis, autism spectrum disorder, and Alzheimer’s disease. The development of IL-17A inhibitors, including the dual IL-17A/F antagonist bimekizumab, has advanced markedly, with demonstrated efficacy in immune-mediated diseases such as psoriasis and psoriatic arthritis. This review provides a comprehensive overview of current knowledge of IL-17A, from its molecular characteristics to clinical applications. Full article

Background: Endogenous opioids, such as endomorphin-2, are key regulators of the body’s pain pathways and mediate analgesia by engaging the $\mu$-opioid receptor. This class of opioids are distinguished by their transient activation of the $\mu$-opioid receptor, which is attributed to rapid enzymatic degradation. Methods: To understand how degradation of endomorphin-2 by the enzyme DPP IV affects its interaction with the $\mu$-opioid receptor, we analyzed the ligand–receptor conformational dynamics and interaction patterns of molecular dynamics simulations data of morphine, fentanyl and endomorphin-2 and one degradation product Phe-Phe-NH₂, using molecular fingerprints and the mathematical framework ISOKANN. Results: Our analyses revealed that both the clinically relevant opioids, morphine and fentanyl, as well as the endogenous opioid endomorphin-2, adopt a set of recurring binding conformations within the $\mu$-opioid receptor binding pocket, maintaining overlapping interaction motifs throughout the simulations. In contrast, Phe-Phe-NH₂ failed to maintain a persistent binding mode over the simulated timescale. This instability arises from the dipeptidyl peptidase IV mediated cleavage of endomorphin-2, which generates Phe-Phe-NH₂ and removes critical proline and tyrosine residues, thereby leading to the loss of stabilizing hydrophobic contacts with receptor residues Tyr150^3,33, Val238^5,43 and Val302^6,55. Conclusion: By mapping structural interaction motifs essential for stable $\mu$-opioid receptor binding, this study provides mechanistic insights into how endogenous degradation reshapes ligand–receptor interactions. Full article

Sickle cell anemia (SCA) is a genetic disorder characterized by chronic hemolysis, primarily driven by red blood cell lysis. Its pathophysiology is centered, though not exclusively, on the increased release of intracellular components, such as hemoglobin degradation products, which are known to stimulate innate immune responses and promote prothrombotic states. Current therapies alleviate symptoms, yet patients remain exposed to a chronic inflammatory milieu punctuated by episodes of acute pain. The recurrence of these crises can be life-threatening due to ischemia–reperfusion injury, hypercoagulability, and respiratory complications. Central mechanisms are marked by elevated hemolysis, heightened inflammatory signaling, and increased procoagulant activity, largely driven by soluble molecules released into the plasma, such as hemoglobin, nuclear molecules and other products. These compounds are recognized from sensors on immune and endothelial cells, named Pattern Recognition Receptors (PRRs), and constitute canonical pathways for intracellular activation. Four main types have been extensively studied in the literature over recent years in both infectious and sterile inflammatory contexts; still, only a few have elucidated the mechanisms underlying acute and chronic inflammation in patients with SCA. Although Toll receptors were shown to be major in triggering immunity, other receptors were found to be important regarding this function, which suggested a multifactorial mechanism for this triggering. Therefore, here, we propose a comprehensive review of previously published findings regarding the expression, activation, and dynamics of Toll-like, NOD-like, and RIG-I–like receptors in the progression of SCA and its associated inflammatory features. Full article

Melatonin is reported to exert two types of actions: those based on its interaction with cognate receptors (characterized by very high affinities—1 nM and below), and those mediated by unknown targets (characterized by high concentrations—100 µM and above). Whereas receptor-mediated activities are known to regulate circadian rhythm, the high-dose effects are reported to be independent of these receptors and to produce literally dozens of beneficial effects in almost all human diseases, including cancer, neurodegenerative disorders, viral infections, obesity and many others. In the present opinion paper, we discuss this extensive set of claims and place them in perspective with a sum of evidence that collectively challenges the validity of these alleged beneficial effects. Full article

Nutrient-sensing nuclear receptors (NSNRs), including PPARs, FXR, LXRs, RAR/RXR, VDR, and related orphan receptors, integrate a molecular interface that allows diet to communicate directly with the genome. By binding fatty acids, bile acids, sterols, vitamins, polyphenols, and other food-derived metabolites, NSNRs translate qualitative and quantitative features of the diet into coordinated transcriptional programmes across metabolically active organs. This ligand-dependent signalling network integrates dietary information to orchestrate inter-organ lipid and glucose metabolism, mitochondrial function, thermogenesis, and immune response, thereby enabling the organism to adapt dynamically to fasting–feeding cycles. In this review, we synthesise current evidence on the integrated roles of major NSNRs in the liver, skeletal muscle, white and brown adipose tissue, and kidney, emphasising how receptor networks within and between metabolic organs collectively govern energy expenditure, substrate partitioning, and systemic metabolic flexibility. We propose a conceptual framework in which diet functions as an “external endocrine organ”, acting as the primary source of chemically diverse NSNR ligands, while metabolic tissues serve as secondary signal amplifiers and integrators. Through circulating lipid species, bile acids, oxysterols, and other metabolites, these organs engage in continuous bidirectional communication that reprograms NSNR activity across tissues. We then examine how the global shift from minimally processed, nutrient-rich foods to nutrient-poor, energy-dense ultra-processed diets leads to a reduction in NSNR ligand diversity, promoting hepatic steatosis, muscle metabolic inflexibility, adipose tissue dysfunction, renal lipotoxicity, and chronic low-grade inflammation, ultimately causing obesity, type 2 diabetes, and cardiometabolic disease. Finally, we explore strategies to restore NSNR function, including Mediterranean and plant-based dietary patterns, as well as diets enriched with ω-3 polyunsaturated fatty acids, monounsaturated fats, and polyphenols. By integrating molecular, physiological, and clinical evidence, this review aims to clarify how NSNR networks translate dietary cues into coordinated inter-organ metabolism and how nutrient-poor diets lead to metabolic diseases trough a loss of metabolic information, rather than merely by energy excess. This framework supports a paradigm shift from calorie-centred nutrition to diet quality as the main therapeutic target for preventing metabolic diseases and promoting health. Full article

FAM3A, FAM3B, FAM3C and FAM3D are members of the “family with sequence similarity 3” (FAM3) gene family, an emerging class of cytokine-like proteins with a unique structural globular β-β-α fold and distinct biological functions. With widespread expression in tissue, organs and in many cell types, their specific roles in human diseases have been the focus of much research. FAM3A acts as a positive regulator of metabolic health, typically activating canonical pro-survival and metabolic pathways. FAM3B, also called PANDER (PANcreatic DERived Factor), exerts critical physiological functions in the regulation of glycemic levels via promotion of hepatic glucose production and pancreatic β-cell insulin secretion. FAM3C, also named ILEI (Interleukin-like EMT inducer), is involved as an inducer of epithelial–mesenchymal transition (EMT) and cancer metastasis, as well as osteoblast differentiation and bone mineralization. FAM3D is a gut-secreted protein and potential regulator of gastrointestinal homeostasis and microbiota-induced inflammation. Here we provide an overview of previous studies supporting that FAM3 proteins act through putative membrane receptors and co-partners, including fibroblast growth factor receptor (FGFR), leukemia inhibitory factor receptor (LIFR), formyl peptide receptor (FPR1/2), to activate diverse downstream signaling pathways on different cellular contexts. Basic and clinical studies suggest that the FAM3 family influences both obesity, diabetes, and other metabolic disorders; thus, its expression may have diagnostic potential. The differential and often cancer-specific expression patterns make members of the FAM3 family promising candidates for biomarkers and therapeutic targets of some types of neoplasia. Full article

The vitamin D receptor (VDR) acts as both a nuclear transcription factor and a non-genomic mediator that regulates a broad spectrum of physiological processes beyond calcium and phosphate homeostasis. VDR plays an important role in the modulation of ion channels across multiple tissues, including osteoblasts, renal and intestinal epithelial cells, neurons, and vascular smooth muscle. These regulatory mechanisms encompass genomic actions through vitamin D response elements in target genes—such as TRPV5, TRPV6, KCNK3, and KCNH1—as well as rapid, non-genomic actions at the plasma membrane involving protein disulfide isomerase A3 and associated signaling cascades. VDR-mediated transcriptional control of calcium, potassium, and chloride channels contributes to the fine-tuning of cellular excitability, calcium transport, and mitochondrial function. Evidence also implicates VDR–ion channel crosstalk in various pathological contexts, including renal cell carcinoma, breast and cervical cancers, pulmonary arterial hypertension, and osteoporosis. Understanding the molecular interplay between VDR and ion channels provides new perspectives on the pleiotropic effects of vitamin D and offers promising therapeutic opportunities in oncology, cardiovascular disease, and skeletal disorders. This review synthesizes previous and current evidence on the genomic and non-genomic mechanisms underlying VDR–ion channel regulation and highlights novel frontiers in vitamin D signaling relevant to human health and disease. Full article