Receptors

The increased prevalence of electronic cigarettes, particularly among adolescents, has escalated concerns about nicotine addiction. Nicotine, a potent psychostimulant found in tobacco products, exerts its effects by interacting with nicotinic acetylcholine receptors (nAChRs) in the brain. Recent findings in both pre-clinical and clinical studies have enhanced our understanding of nAChRs, overcoming the limitations of pharmacological tools that previously hindered their investigation. Of particular interest is the α6 subunit, whose expression peaks during adolescence, a critical period of brain development often marked by the initiation of substance use. Pre-clinical studies have linked α6-containing nAChRs (α6*nAChRs) to nicotine-induced locomotion, dopamine release, and self-administration behavior. Furthermore, clinical studies suggest an association between the α6 subunit and increased smoking behavior in humans. Specifically, a single nucleotide polymorphism in the 3′ untranslated region of the CHRNA6 gene that encodes for this subunit is linked to smoking behavior and other substance use. A comprehensive understanding of this subunit’s role in addiction is of high importance. This review aims to consolidate current knowledge regarding the α6 subunit’s functions and implications in addiction and other disorders, with the hope of paving the way for future research and the development of targeted therapies to address this pressing public health concern. Full article

Background: Lysophosphatidic acid (LPA) receptor 3 (LPA₃) is involved in many physiological and pathophysiological actions of this bioactive lipid, particularly in cancer. The actions of LPA and oleoyl-methoxy glycerophosphothionate (OMPT) were compared in LPA₃-transfected HEK 293 cells. Methods: Receptor phosphorylation, ERK 1/2 activation, LPA₃-β-arrestin 2 interaction, and changes in intracellular calcium were analyzed. Results: Our data indicate that LPA and OMPT increased LPA₃ phosphorylation, OMPT being considerably more potent than LPA. OMPT was also more potent than LPA to activate ERK 1/2. In contrast, OMPT was less effective in increasing intracellular calcium than LPA. The LPA-induced LPA₃-β-arrestin 2 interaction was fast and robust, whereas that induced by OMPT was only detected at 60 min of incubation. LPA- and OMPT-induced receptor internalization was fast, but that induced by OMPT was more marked. LPA-induced internalization was blocked by Pitstop 2, whereas OMPT-induced receptor internalization was partially inhibited by Pitstop 2 and Filipin and entirely by the combination of both. When LPA-stimulated cells were rechallenged with 1 µM LPA, hardly any response was detected, i.e., a “refractory” state was induced. However, a conspicuous and robust response was observed if OMPT was used as the second stimulus. Conclusions: The differences in these agents’ actions suggest that OMPT is a biased agonist. These findings suggest that two binding sites for these agonists might exist in the LPA₃ receptor, one showing a very high affinity for OMPT and another likely shared by LPA and OMPT (structural analogs) with lower affinity. Full article

Background: Nitric oxide (NO) is a gaseous molecule considered to be a protagonist in the dilation of blood vessels, and its property and/or bioavailability are reduced in pathophysiological conditions such as cardiovascular diseases. Therefore, its exogenous administration becomes attractive, and new classes of compounds able to induce NO release have emerged to minimize the adverse effects found by existing NO donor drugs. Objective: Our aim was to investigate the vasorelaxant effect and mechanism of action induced by the ruthenium complex, which contains nitric oxide in its structure, [Ru(phen)₂(TU)NO](PF₆)₃ (FOR 911B), in isolated rat aorta. Methods: The animals were euthanized, and the aorta artery was identified, removed, and immediately placed in modified Krebs–Henseleit solution. To verify tissue viability, a contraction was obtained with phenylephrine (Phe) (0.1 μM), and to assess endothelial integrity, acetylcholine (ACh) (1 μM) was added. Results: In the present study, we demonstrated, for the first time, that FOR 911B promotes vasorelaxation in a concentration-dependent manner in isolated rat aortic artery rings. After the removal of the vascular endothelium, the potency and efficacy of the relaxation were not altered. With pre-incubation with hydroxocobalamin, the relaxing response was abolished, and with the use of ODQ, the main NO receptor blocker, the vasorelaxant effect was attenuated with a shift of the curve to the right. To investigate the participation of K⁺ channels, the solution concentration was changed to KCl (20 and 60 mM), and it was pre-incubated with the non-selective K⁺ channels blocker (TEA). Under these conditions, relaxation was altered, demonstrating that K⁺ channels are activated by FOR 911B. By selectively blocking the different subtypes of K⁺ channels with specific blockers, we demonstrated that the subtypes K_V, K_IR, SK_Ca, and BK_Ca are involved in the vasodilator effect induced by FOR 911B. Conclusions: The results obtained demonstrated that FOR 911B promotes vascular relaxation in aortic artery rings in a concentration-dependent manner and independent of the vascular endothelium through the participation of the NO/sGC/cGMP pathway, as well as with the involvement of different K⁺ channels. Full article

Work with novel indicators that report intracellular ATP concentrations with improved spatial and temporal resolution have challenged the current consensus that under physiological conditions, intracellular ATP concentrations are not rate-limiting to enzymatic reactions. Recent data from cardiac myocytes and cultured neurons show marked fluctuations of intracellular ATP levels, as well as evidence for compartmentalization. It is likely that the availability of these genetically encoded indicators will produce rapid progress in the mapping of the dynamics of intracellular ATP concentrations in various types of cells. Here, a brief account of the most recent indicators is provided as well as a review of how natural evolution appears to have obviated the potential shortage of the ATP supply to one of key enzymes of the cyclic AMP signaling cascade, adenylyl cyclase 9. Full article

Reactive oxygen species (ROS) encompass various molecular oxygen derivatives naturally produced during aerobic metabolism, including superoxide anions, hydrogen peroxide, and hydroxyl radicals. Excessive ROS production leads to oxidative distress, causing cellular damage and contributing to various pathologies, often alongside inflammation. Endogenous sources of ROS include mitochondrial activity and NADPH oxidases. The antioxidant system, comprising enzymes such as superoxide dismutase, peroxiredoxin, and catalase, mitigates ROS-induced damage. This review explores the regulation of ROS by membrane receptors, focusing on B1 and B2 kinin receptors and histamine H2 receptors, which are implicated in vasodilation, angiogenesis, inflammation, and gastric acid secretion. Understanding these interactions provides insights into ROS modulation and its role in disease mechanisms. Full article

Prostate cancer (PCa) is the most prevalent cancer among men globally. In addition to environmental risk factors, genetic factors play a crucial role in its development and progression, highlighting the regulation of key genes as an essential aspect. The androgen receptor gene (AR) plays a pivotal role in this disease, so its post-transcriptional regulation must be meticulously coordinated. In this review, we explore the role of microRNAs (miRNAs) in the regulation of AR in PCa, a field not yet fully investigated. We note that the AR, due to its extensive 3′UTR region, is targeted by numerous miRNAs, and that this regulation can occur at different levels: directly, indirectly, and through mutual regulation, thus amplifying the influence of these molecules on AR regulation. Full article

Amino acid transporters play pivotal roles in cancer biology, including in urological cancers. Among them, L-type amino acid transporter 1 (LAT1), alanine-serine-cysteine transporter 2 (ASCT2), and cystine-glutamate transporter (xCT) have garnered significant attention due to their involvement in various aspects of tumor progression and response to therapy. This review focuses on elucidating the regulation and functions of these amino acid transporters in urological cancers, including prostate, bladder, and renal cancers. Understanding the intricate regulatory mechanisms governing these amino acid transporters is essential for developing effective therapeutic strategies. Furthermore, exploring their interactions with signaling pathways and microenvironmental cues in the context of urological cancers may uncover novel therapeutic vulnerabilities. This comprehensive overview highlights the importance of amino acid transporters, particularly LAT1, ASCT2, and xCT, in urological cancers and underscores the potential of their inhibitors as therapeutic targets for improving patient outcomes. Full article

Folate receptor alpha (FRα) is a glycosylphosphatidylinositol (GPI) membrane-anchored protein containing three N-glycosylated residues at the N47, N139, and N179 termini. These glycosylation sites have been reported to be crucial for the receptor’s structural integrity and its ability to bind and internalize FA. Here, we investigated the role of FRα glycosylation in the binding and internalization efficacy of FA–DABA–SMA in pancreatic PANC-1 cancer cells. There is a strong association of the FA copolymer with FRα with a Pearson coefficient R-value of 0.7179. PANC-1 cancer cells were pretreated with maackia amurensis lectin II (MAL-2), sambucus Nigra lectin (SNA-1), peanut agglutinin (PNA), and wheat germ agglutinin lectin (WGA) at different doses followed by 20 kDa and 350 kDa FA–DABA–SMA loaded with coumarin 153 (C153). Increasing the dosage of MAL2, SNA-1, PNA, and WGA concomitantly and significantly increased the internalization of C153-loaded FA–DABA–SMA in the cells. The half maximal effective lectin concentrations (EC50) to induce cellular internalization into the cytoplasm of the lectins for MAL-2 were 35.88 µg/mL, 3.051 µg/mL for SNA-1, 7.883 µg/mL for PNA, and 0.898 µg/mL for WGA. Live cell imaging of the internalization of 20 kDa and 350 kDa FA copolymers indicated an aggregation of 350 kDa copolymer with FRα in the cytoplasm. In contrast, the 20 kDa FA copolymer remained in the membrane. The data indicate for the first time that the mobile positions of the glycosyl radical groups and the receptor tilt in generating steric hindrance impacted the individual FRα receptors in the binding and internalization of 350 kDa FA–DABA–SMA in cancer cells. Full article

This review focuses on the pivotal roles of nuclear receptors (NRs) in driving endocrine resistance in prostate and breast cancers. In prostate cancer (PCa), androgen receptor (AR) amplification, mutations, and altered coactivator interactions sustain tumor growth under androgen deprivation therapy (ADT), leading to castration-resistant prostate cancer (CRPC). Orphan NRs like RORβ, TLX, and COUP-TFII further contribute to CRPC by regulating stemness and therapeutic resistance mechanisms. In breast cancer, NRs, including estrogen receptor alpha (ERα), androgen receptor (AR), glucocorticoid receptor (GR), and liver receptor homolog-1 (LRH-1), modulate estrogen signaling pathways and alternative survival mechanisms like PI3K/AKT/mTOR and NFκB, promoting resistance to endocrine therapies such as tamoxifen. Understanding these NR-mediated mechanisms is critical for developing targeted therapies to overcome endocrine resistance and improve patient outcomes in hormone-dependent cancers. Full article

This review article explores the fundamental role of receptor targeting in overcoming drug resistance in cancer therapy, an area of critical concern given the persistently high rates of cancer morbidity and mortality globally. We highlight how receptor biology intersects with the development of therapeutic resistance with a specific focus on anti-angiogenic agents, immune checkpoint inhibitors, and monoclonal antibodies, which directly or indirectly influence receptor pathways. We also explore how other receptor tyrosine kinases can initially suppress tumor growth, yet often lead to resistance, underscoring the need for novel combinatorial approaches that incorporate advanced receptor modulation techniques. Further, the review delves into the mechanisms by which modulation of the tumor microenvironment and immune system via receptor pathways can overcome resistance to traditional immunotherapies. Additionally, emerging technologies in receptor-targeted nanomedicine are also highlighted, showcasing their potential to revolutionize drug delivery and improve therapeutic outcomes by targeting specific receptor interactions. Ultimately, this review calls for a deeper understanding of receptor dynamics to develop more precise interventions, including insights from various healthcare settings that can prevent or circumvent drug resistance, thus enhancing patient outcomes in oncology. Full article

Post-translational protein modifications (PTMs) significantly enhance the functional diversity of proteins and are therefore important for the expansion and the dynamics of the cell’s proteome. In addition to structurally simpler PTMs, substrates also undergo modification through the reversible attachment of small proteins. The best understood PTM of this nature to date is the covalent conjugation of ubiquitin and ubiquitin-like proteins (UBLs) to their substrates. The protein family of small ubiquitin-like modifier (SUMO) is one of these UBLs that has received increasing scientific attention. The pathway of SUMOylation is highly conserved in all eukaryotic cells and is crucial for their survival. It plays an essential role in many biological processes, such as the maintenance of genomic integrity, transcriptional regulation, gene expression, and the regulation of intracellular signal transduction, and thereby influences DNA damage repair, immune responses, cell cycle progression, and apoptosis. Several studies have already shown that in this context protein SUMOylation is involved in the control mechanisms of various cellular receptors. This article unites data from different studies focusing on the investigation of the strictly conserved three-step enzyme cascade of protein SUMOylation and the functional analysis of the involved proteins E1, E2, and E3 and SUMOylation target proteins. Furthermore, this review highlights the role of nuclear receptor SUMOylation and its importance for the cellular functionality and disease development arising from defects in correct protein SUMOylation. Full article

Chronic skin wounds are estimated to affect 6.5 million patients in the US, at a cost of over USD 25 billion. Efforts to prevent and/or treat such wounds will result in reduced morbidity and economic losses. This project is focused on the role of vitamin D signaling in the epidermis in the control of stem cell (SC) activation and function during the initial response to the wounding of the skin, a response that, if defective, contributes to poor wound healing or cancer. In this review, I first describe the anatomy of the skin, focusing first on the epidermis, describing the different cell layers which in a spatial way also represent the differentiation process of the interfollicular epidermis (IFE) as it undergoes continuous regeneration. I then describe the other components of the skin, particularly the hair follicle (HF), which undergoes a cyclic pattern of regeneration. Adult SCs residing in these regenerative tissues play essential roles in the maintenance of these tissues. However, when the skin is wounded, the progeny of SCs from all regions of the HF and IFE contribute to the healing process by changing their initial cell fate to take on an epithelial genotype/phenotype to heal the wound. Although earlier lineage tracing studies helped to define the contributions SCs from the different niches made to wound healing, scRNAseq studies have demonstrated a considerably more nuanced picture. The role of vitamin D signaling will be introduced by reviewing the unique role played by the epidermal keratinocyte first in producing vitamin D and then in metabolizing it into its active form 1,25(OH)2D. 1,25(OH)2D is the principal ligand for the vitamin D receptor (VDR), a transcription factor that helps to mediate the genomic changes in the stem cells in their response to wounding. In these actions, the VDR is regulated by coregulators, of which the steroid receptor coactivator complexes SRC 2 and 3 and the mediator complex (MED) play essential roles. The VDR generally acts in association with other transcription factors such as p63 and β-catenin that can colocalize with the VDR in the genes it regulates. Although much remains to be understood, the role of the VDR in the stem cell response to wounding is clearly essential and quite different from its classic roles in regulating calcium metabolism, although calcium is essential for the actions of vitamin D signaling in the skin. Full article

Human endocannabinoid signaling is primarily mediated by the cannabinoid receptors, CB1 and CB2, which are G protein-coupled receptors (GPCRs). These receptors have been linked to a variety of physiological processes and are being pursued as prospective drug targets due to their potential in treating pain and inflammation. However, because of their homology and shared signaling mechanisms, investigating the individual physiological roles of these receptors and designing subtype-selective ligands has been challenging. Using active-state CB1 and CB2 structures as guides, homologous residues within the orthosteric pocket of each receptor were mutated to alanine to test whether they equally impair CB1 and CB2 activity in response to two high-affinity, nonselective agonists (CP55,940 and AM12033). Interestingly, mutating the Y5.39 position impairs CB1 but not CB2 function. Conversely, mutating residue C6.47 improves CB1 but impairs CB2 signaling. The F7.35A mutation leads to a decrease in CP55,940 potency at CB1 and impairs internalization; however, AM12033 gains potency and promotes CB1 internalization. In CB2, mutation of F7.35A decreases the potency of CP55,940 and neither agonist induces internalization. These observations provide some insight into functional sensitivity of CB1 and CB2 to different agonists when conserved residues are mutated in the orthosteric pocket. Full article

Overweight and obesity are global health and economic concerns. This disease can affect every system of the human body and can lead to complications such as metabolic syndrome, diabetes, cancer, dyslipidemia, cardiovascular diseases, and hypertension, among others. Treatment may sometimes include diet, exercise, drugs, and bariatric surgery. Nonetheless, not all people have access to these treatments, and public health strategies consider prevention the most important factor. In this regard, recent investigations are aiming to find alternatives and adjuvants for the treatment of obesity, its prevention, and the reversion of some of its complications, using natural sources of anti-obesogenic compounds like polyphenols, terpenes, alkaloids, and saponins, among others. In this review, we gather the most current information using PubMed, Google Scholar, Scopus, Cochrane, and the Web of Science. We present and discuss the current information about natural products that have shown anti-obesogenic effects at a molecular level. We also consider the impact of dietary habits and lifestyle on preventing overweight and obesity due to the evidence of the benefits of certain foods and compounds consumed regularly. We discuss mechanisms, pathways, and receptors involved in the modulation of obesity, especially those related to inflammation and oxidative stress linked to this disease, due to the relevance of these two aspects in developing complications. Full article

Receptor-targeted drug delivery has been extensively explored for active targeting of therapeutic moiety in cancer treatment. In this review, we discuss the receptors that are overexpressed on tumor cells and have the potential to be targeted by nanocarrier systems for cancer treatment. We also highlight the different types of nanocarrier systems and targeting ligands that researchers have explored. Our discussion covers various therapeutic modalities, including small molecules, aptamers, peptides, antibodies, and cell-based targeting strategies, and focuses on clinical developments. Additionally, this article highlights the challenges that arise during the clinical translation of nanocarrier-based targeting strategies. It also provides future directions for improving research in the area of clinically translatable cancer-targeted therapy to improve treatment efficacy while minimizing toxicity. Full article

Liver X receptors (LXRs) are members of the nuclear receptor superfamily of ligand-dependent transcription factors. LXRα is predominantly expressed in metabolic tissues, whereas LXRβ is ubiquitously expressed. Upon ligand binding, they regulate the expression of target genes involved in lipid metabolism, cholesterol homeostasis, and immune responses, including those which function in pathways that are commonly reprogrammed during carcinogenesis. Known LXR ligands include oxysterols and natural and synthetic agonists which upregulate LXR transcriptional activity and target gene expression. Synthetic inverse agonists have also been identified that inhibit LXR activity. While both types of ligands have been shown to inhibit cancer cells and tumor growth either directly or indirectly by modulating the activities of stromal cells within the tumor microenvironment, they appear to target different aspects of cancer metabolism and other cancer hallmarks, including immune evasion. This review summarizes the characterization of LXRs and their ligands and their mechanisms of action in cancer models and discusses the future directions for translating these discoveries into novel cancer therapeutics. Full article

For humans to explore and colonize the universe, both engineering and physiological obstacles must be successfully addressed. A major physiological problem is that humans lose bone rapidly in microgravity. Understanding the underlying mechanisms for this bone loss is crucial for designing strategies to ameliorate these effects. Because bone physiology is entangled with other organ systems, and bone loss is a component of human adaptation to microgravity, strategies to reduce bone loss must also account for potential effects on other systems. Here, we consider the receptors involved in normal bone remodeling and how this regulation is altered in low-gravity environments. We examine how single cells, tissues and organs, and humans as a whole are affected by low gravity, and the role of receptors that have been implicated in responses leading to bone loss. These include receptors linking cells to the extracellular matrix and to each other, alterations in the extracellular matrix associated with changes in gravity, and changes in fluid distribution and fluid behavior due to lack of gravity that may have effects on receptor-based signaling shared by bone and other regulatory systems. Inflammatory responses associated with the environment in space, which include microgravity and radiation, can also potentially trigger bone loss. Full article

Insect-transmitted plant viruses are a major threat to global agricultural crop production. Receptors play a prominent role in the interplay between host-pathogen and vector interaction. The virus–vector relationship involves both viral and vector receptors. Receptors-like kinases (RLKs) and receptor-like proteins play a crucial role in plant immunity, which acts as a basal defense. Pathogens can evade or block host recognition by their effector proteins to inhibit pathogen recognition receptor (PRR)-mediated signaling. Intriguingly, RLKs are also known to interact with viral proteins and impact plant susceptibility against viruses, while the endocytic receptors in vectors assist in the binding of the virus to the vectors. Unlike other receptors of fungi and bacteria which have three different domains located from extracellular or intracellular to perceive a multitude of molecular patterns, the characterization of viral receptors is quite complex and limited since the virus is directly injected into plant cells by insect vectors. Little is known about these receptors. Unraveling the receptors involved in virus entry and transmission within the vector will provide vital information in virus–vector interactions. This review focuses on efforts undertaken in the identification and characterization of receptors of plant viruses within the host and vector. This will lead to a better understanding of the cellular mechanism of virus transmission and spread, and further suggests new alternative tools for researchers to develop an integrated approach for the management of viral diseases and associated vectors. Full article

The high incidence of cancer and the prevalence of chemoresistance are serious problems worldwide, underscoring the urgency of novel research focused on understanding the underlying mechanisms and finding new therapeutic targets. Recently, the G protein-coupled estrogen receptor (GPER) has received increasing attention, and it has been studied in various models, including physiological and pathological conditions, using appropriate pharmacological and molecular biological strategies. Numerous studies indicate that GPER plays an important role in cancer progression and resistance. This review focuses on the structure of GPER, the diversity of its ligands and GPER-activated signaling pathways, the role of GPER in cancer progression, and mechanisms of chemoresistance, with special emphasis on different cancer types and the tumor microenvironment. GPER was evidenced to exhibit conformational plasticity and different ligand binding modes. Therefore, GPER-mediated effects can be triggered by estrogens or various estrogen mimetics, including synthesized compounds, licensed drugs, or exogenous environmental compounds. We found multiple reports evidencing that GPER is differentially expressed in healthy tissues and tumors and plays a protumor role in breast, ovarian, lung, thyroid, and endometrial cancers. Additionally, there are several studies that indicate that GPER expression in cells of the tumor microenvironment may also contribute to cancer progression. Among the major mechanisms of GPER-mediated chemoresistance are the epithelial-mesenchymal transition, the overexpression of multidrug resistance pumps, and autophagy regulation. Full article