Receptors, Volume 4, Issue 4 (December 2025) – 7 articles

Transient Receptor Potential Vanilloid (TRPV) channels represent one of the seven subfamilies of TRP receptors and are widely expressed throughout the human body where they play pivotal roles in various physiological processes. In the gastrointestinal (GI) system, TRPV channels regulate critical functions such as nutrient absorption, motility, and secretions. Beyond maintaining cellular homeostasis, these channels are involved in pain and inflammation, contributing to diverse pathologies. Their central role in the pathophysiology of different digestive system disorders has made TRPV channels a significant focus of research. Moreover, the involvement of TRPV channels in numerous GI cancers has further heightened research interest in the role of these channels. Accordingly, this review elucidates the structural components and intricate signaling pathways of TRPV channels, focusing on the unique characteristics of each family member (TRPV1–6) in GI physiology. Furthermore, we explore the therapeutic potential of targeting these channels to modulate their physiological and pathological roles, highlighting their promise in treating GI disorders. Additionally, we address the challenges associated with their therapeutic application, considering their interactions in different systems, inherent biochemical characteristics, and the alterations required for effective design. Full article

Injury to tissue induces the normal wound healing process to repair damage. This is a normal and critical response developed by the body to maintain short-term organ function, and therefore, survival. Should this process become aberrant, then fibrosis can develop. Fibrosis is the excess accumulation of extracellular matrix proteins. Unlike normal wound healing that is designed to maintain organ/tissue function, fibrosis interferes with the normal architecture of the organ and has long-term functional implications. Fibroblasts are the cells responsible for producing extracellular matrix in both wound healing and fibrosis. Substance P is the cognate ligand for the neurokinin-1 receptor, and both substance P and the neurokinin-1 receptor have been demonstrated to be involved in organ remodeling; this includes regulation of fibroblast function. In this review we will focus on substance P/neurokinin-1 receptor regulation of fibroblast function in the setting of both wound healing and fibrosis. This review describes actions of substance P and the neurokinin-1 receptor on fibroblasts from multiple organs, thus identifying central actions common to all fibroblasts studied. This review also identifies gaps in the literature and future directions needed to improve understanding of substance P and the neurokinin-1 receptor regulation of fibroblast phenotype. Full article

Cannabinoids, compounds that interact with the endocannabinoid system, have shown promising neuroprotective effects in various neurodegenerative diseases, including those affecting the retina. This review evaluates evidence for the presence and action of cannabinoids in the retina, their function in protecting against oxidative stress and modulating neuroinflammation, and the outcomes observed in animal models of retinal diseases such as glaucoma and age-related macular degeneration (AMD), the most common causes of vision loss. Cannabinoids have proven effective in reducing the neurodegeneration seen in these eye diseases, acting via the CB1 and CB2 cannabinoid receptors. The cannabinoid neuroprotective effect is often of a similar magnitude to the other proven therapy of medical dosage of vitamins, though it confers a greater risk due to neurotoxicity with high THC:CBD ratios, making the vitamin therapy of greater efficacy when time is available. Given the increased ratio of THC:CBD in commercial cannabis strains, rising from 10:1 at the beginning of this century to 100:1 now, the risk of neurotoxicity has increased, reducing the neuroprotective benefit. The proven safety and efficacy of vitamin therapy may be a more viable neuroprotective method than cannabinoid use for chronic conditions, with cannabinoids proving their utility in more acute conditions. This review evaluates both the method of action of cannabinoids and the receptor pathway utilized and compares the suggested therapeutic applicability of cannabinoids with proven vitamin therapy. Full article

Both primary and secondary hemostasis consist of finely regulated pathways, forming a blood clot to stop bleeding. These orchestrated mechanisms involve multiple plasma- and platelet/endothelial-derived receptors, factors, enzymes, and proteins, such as the von Willebrand factor (vWF), fibrinogen, and thrombin. Over-activation or improper resolution of the coagulation cascade leads to severe pathological disorders, arterial and venous. Despite the fact that the genetic etiology of thrombophilia has gained the main research interest, there is growing evidence that the disturbed redox network of key hemostatic pathways signals thrombus formation. Oxidized LDL in dyslipidemias and many endogenous and exogenous compounds act as pro-oxidant stimuli that lead to post-translational modifications of proteins, such as sulfenylation, nitrosation, disulfide formation, glutathionylation, etc. Oxidation of cysteine and methionine residues of vWF, fibrinogen, and thrombomodulin has been detected at thrombotic episodes. Increased homocysteine levels due to, but not restricted to, methylenetetrahydrofolate reductase gene (MTHFR) mutations have been incriminated as a causative factor for oxidative stress, leading to a pro-thrombotic phenotype. Alterations in the vascular architecture, impaired vascular relaxation through decreased bioavailability of NO, accumulation of Nε-homocysteinylated proteins, ER stress, and endothelial cells’ apoptosis are among the pro-oxidant mechanisms of homocysteine. This review article focuses on describing key concepts on the oxidant-based molecular pathways that contribute to thrombotic episodes, with emphasis on the endogenous compound, homocysteine, aiming to promote further molecular, clinical, and pharmacological research in this field. Full article

Background: PIEZO channels are mechanoreceptors expressed in various cells. Their contributions to animal development are not entirely clear. According to the physical distortion hypothesis, developmental organizers for butterfly wing eyespots receive and release mechanical signals in pupal wing tissues during development, initiating a calcium signaling cascade and gene expression changes. Objectives: We tested the possible involvement of PIEZO1 in butterfly wing color pattern formation, according to the physical distortion hypothesis. Methods: We performed a pharmacological intervention of PIEZO1, focusing on the eyespots of Junonia orithya. Chemical modulators of PIEZO1 and the actin cytoskeleton were injected into pupae immediately after pupation during the critical period of color pattern determination, and the eyespot color patterns of the emerging adult wings were analyzed. We also tested dimethyl sulfoxide (DMSO) because it was used as a solvent. Results: DMSO significantly enlarged most eyespots examined. In contrast, the specific PIEZO1 activator Jedi2 induced significant reduction in the dorsal hindwing eyespots. Another specific PIEZO1 activator, Yoda1, also induced similar changes, although less clearly. The mechanosensitive channel blocker GsMTx4 produced compromised eyespots in an individual, although statistical support for modification was weak. The actin polymerization activator phalloidin induced blue foci in the ventral forewing eyespots. PIEZO expression in the pupal wings was demonstrated by RT-PCR. Conclusions: These results suggest that eyespot organizers in butterfly wings may employ a PIEZO-mediated mechanotransduction pathway to regulate eyespot color patterns, supporting the physical distortion hypothesis. These results highlight the importance of PIEZO in developmental organizers in animals. Full article

Adipocyte cell models are essential for investigating adipogenesis, yet methodological inconsistencies pose challenges to obtaining reproducible and physiologically relevant results. Murine cell lines, such as 3T3-L1 and OP9, are commonly utilized due to their established adipogenic capabilities. However, differences in its metabolic, genetic regulation, and receptor signaling raise concerns about their applicability to human adipose biology. Human-derived models, including mesenchymal stem cells (hMSCs) and preadipocyte cell lines, offer a closer approximation to in vivo adipogenesis but display significant variability in differentiation efficiency. This variability is often compounded by heterogeneous differentiation protocols, variations in cell confluence, and unstandardized pharmacological induction strategies. A pivotal factor influencing adipogenic potential is the receptor toolkit, which dictates cellular responses to differentiation stimuli. This study systematically evaluates key receptors—PPARγ, glucocorticoid receptors (GR), insulin receptor (IR), thyroid hormone receptors (TR), estrogen receptors (ER), and adenosine receptors (AR)—across commonly used adipocyte models to assess their roles in adipogenic regulation. Additionally, we examine the impact of pharmacological agents capable of inducing adipogenesis (adipogens) and the methodological inconsistencies that contribute to variations in adipocyte differentiation. By addressing these factors, we aim to elucidate the extent to which receptor variability influences experimental outcomes and propose a more structured approach to interpreting adipogenesis research. This critical assessment underscores the need for greater methodological transparency and receptor profiling to enhance the reliability of adipocyte models in metabolic research. Standardizing differentiation methodologies while accounting for receptor diversity will be essential for refining in vitro models and improving their translational potential in the study of obesity, diabetes, and other metabolic disorders. Full article

Background: HER1 and HER2 are critical receptors involved in tumorigenesis and the development of targeted therapies for various carcinomas. However, most antibodies and drugs currently in development do not recognize murine orthologs, which restricts their evaluation in immunocompetent models. Methods: We generated nine tumor models through the lentiviral transduction of murine prostate (RM1), lung (3LL-D122), and breast (4T1) carcinoma cell lines, subsequently validating them in immunocompetent BALB/c and C57BL/6 hosts. Receptor expression and functionality were characterized using flow cytometry, immunoblotting, proliferation assays, and therapeutic sensitivity testing. Results: Transduced cells exhibited stable membrane expression of HER1/HER2 and ligand-induced phosphorylation, confirming receptor functionality. In all three tumor models generated, the expression of HER1 and/or HER2 significantly enhanced cell proliferation compared to parental lines. Furthermore, treatment with specific monoclonal antibodies and the tyrosine kinase inhibitor markedly reduced the viability of cells expressing HER1 and/or HER2, without affecting negative controls. Conclusions: These models provide a robust and reproducible platform for the preclinical evaluation of HER1/HER2-targeted therapies in immunocompetent hosts. Although the current model relies on subcutaneous implantation and does not fully replicate the native tumor microenvironment, it represents a crucial first step toward the development of orthotopic and immunologically relevant models for translational cancer research. Full article