Receptors

Mutations in hormone receptors significantly influence infertility and the outcomes of assisted reproductive technologies (ART). This review explores the functional interplay among mutations in FSHR, LHCGR, AR, ESR1, and ESR2 hormone receptors and their combined effects on hormonal regulation, ovarian response, and implantation. Rather than analyzing receptor mutations in isolation, we explore how mutations in these genes interact within a complex hormonal signaling network, shaping reproductive outcomes. We detail the molecular mechanisms of receptor dysfunction, their associated clinical phenotypes, and the role of genetic screening in guiding personalized ART protocols. A comprehensive understanding of these interactions is crucial for optimizing treatment strategies, improving reproductive success, and advancing targeted therapeutic approaches in reproductive medicine. Full article

Boron-containing compounds (BCCs) have emerged as potential drugs. Their drug-like effects are mainly explained by their mechanisms of action in enzymes. Nowadays, some experimental data support the effects of specific BCCs on GPCRs, provided there are crystal structures that show them bound to G protein-coupled receptors (GPCRs). Some BCCs are recognized as potential ligands of GPCRs—the drug targets of many diseases. Objective: The aim of this study was to collecte up-to-date data on the interactions of BCCs with GPCRs. Methods: Data were collected from the National Center of Biotechnology Information, PubMed, Global Health, Embase, the Web of Science, and Google Scholar databases and reviewed. Results: Some experimental reports support the interactions of BCCs with several GPCRs, acting as their labels, agonists, or antagonists. These interactions can be inferred based on in silico and in vitro results if there are no available crystal structures for validating them. Conclusions: The actions of BCCs on GPCRs are no longer hypothetical, as the existing evidence supports BCCs’ interactions with and actions on GPCRs. Full article

Dictyostelium discoideum (Dicty) is a type of unicellular amoeba, but when starved, a large number of amoebas gather together to form a multicellular organism. In this review, we first introduce our cellular dynamics method for Dicty, including intracellular biochemical reactions. We then introduce a number of hidden roles of receptors revealed by our simulation studies. Of particular note is that receptor–receptor interactions are strengthened under starvation conditions, resulting in diverse dynamic functions that cannot be predicted from the action of a single receptor, such as intercellular synchronization. Furthermore, we introduce a mathematical generalization of Dicty’s receptor function and demonstrate its potential applications not only in the biological field but also in the engineering field. Full article

Skeletal muscle aging, or sarcopenia, involves progressive muscle mass and function loss, which limits mobility and independence in elderly populations. This decline is driven by chronic inflammation, oxidative stress, and insulin resistance, all of which impair muscle regeneration and accelerate protein breakdown. Mineralocorticoid receptors (MRs), known for their roles in electrolyte balance, have emerged as key regulators of these processes in skeletal muscle. MR activation promotes inflammatory signaling, increases oxidative stress, and worsens insulin resistance, accelerating sarcopenia progression. This review examines the impact of MRs on muscle health and highlights the therapeutic potential of targeting these receptors to counteract age-related muscle loss. MR antagonists, such as spironolactone, show promise in reducing inflammation and oxidative damage, potentially slowing sarcopenia. Physical exercise, an established intervention for muscle health, may enhance MR antagonism effects by improving insulin sensitivity and reducing inflammation. However, more research is needed to determine the efficacy and safety of combined MR antagonists and exercise protocols for preventing sarcopenia in older adults. Full article

Background: The development of cerebral organoids created from human pluripotent stem cells in 3D culture may greatly improve the discovery of neuropsychiatric medicines. Methods: In the current study we differentiated neural organoids from a human pluripotent stem cell line in vitro, recorded the development of neurophysiological activity using multielectrode arrays (MEAs) and characterized the neuropharmacology of synaptic signaling over 8 months in vitro. In addition, we investigated the ability of these organoids to display epileptiform activity in response to a convulsant agent and the effects of antiseizure medicines to inhibit this abnormal activity. Results: Single and bursts of action potentials from individual neurons and network bursts were recorded on the MEA plates and significantly increased and became more complex from week 7 to week 30, consistent with neural network formation. Neural spiking was reduced by the Na channel blocker tetrodotoxin but increased by the inhibitor of K_V7 potassium channels XE991, confirming the involvement of voltage-gated sodium and potassium channels in action potential activity. The GABA antagonists bicuculline and picrotoxin each increased the spike rate, consistent with inhibitory synaptic signaling. In contrast, the glutamate receptor antagonist kynurenic acid inhibited the spike rate, consistent with excitatory synaptic transmission in the organoids. The convulsant 4-aminopyridine increased spiking, bursts and synchronized firing, consistent with epileptiform activity in vitro. The anticonvulsants carbamazepine, ethosuximide and diazepam each inhibited this epileptiform neural activity. Conclusions: Together, our data demonstrate that neural organoids form inhibitory and excitatory synaptic circuits, generate epileptiform activity in response to a convulsant agent and detect the antiseizure properties of diverse antiepileptic drugs, supporting their value in drug discovery. Full article

Odorant receptors (ORs) constitute the largest family of G protein-coupled receptors (GPCRs), with nearly 400 receptors identified in humans. The “omics” era has revealed an unexpected expression of ORs beyond olfactory tissues. For many decades these receptors were neglected from cancer research, largely due to the assumption that their expression in cancerous tissues was a background leakage, unrelated to conventional cancer pathways such as cell replication, differentiation, or DNA damage response. The Cancer Genome Atlas (TCGA) data shows, however, that OR expression profiles are specific to each tumor type. This evidence supports that ORs may be related to tumor malignancy. In this review, we explore the extranasal expression of ORs in cancer and discuss the potential implications of their presence in cancerous tissues. Full article

Background/Objectives: Gelsolin (GSN) is an actin-binding protein that helps maintain neuronal structure and shape, regulates neuronal growth, and apoptosis. Our previous work demonstrated that GSN associated with estrogen receptor beta (ERβ1) in the brains of female rats, but this association was lost in advanced age. GSN was also required for ERβ1-mediated transcriptional repression at activator protein-1 (AP-1) motifs upstream of a minimal gene promoter. However, the consequences of the loss of GSN:ERβ1 protein interaction on ERβ1 nuclear translocation and transcriptional repression at AP-1 sites located within complex endogenous gene promoters remained unclear. Methods: We used immunofluorescent super resolution microscopy and luciferase reporter assays to test the hypothesis that GSN facilitates ERβ1 nuclear translocation and transcriptional repression of two genes relevant for Alzheimer Disease: APP (amyloid-beta precursor protein) and ITPKB (inositol-1,4,5-trisphosphate 3-kinase B). Results: Our results revealed the novel finding that GSN is required for ERβ1 ligand-independent nuclear translocation in neuronal cells. Moreover, we show that GSN increased APP and ITPKB promoter activity, which was repressed by ERβ1. Conclusions: Together, these data revealed the importance of the cytoskeletal protein, GSN, in regulating intracellular trafficking of nuclear receptors and demonstrate the first evidence of ERβ1 directly regulating two genes that are implicated in the progression of AD. Full article

Bioelectric membrane potentials regulate cellular growth, differentiation, and movement. Disruptions in bioelectric signaling are strongly linked to cancer development, as abnormal membrane potentials and ion channel activity can drive tumor progression. In breast cancer, ion channel dysfunction and neuroreceptor-related pathways play significant roles in the cell cycle, epithelial–mesenchymal transition, angiogenesis, inflammation, the tumor microenvironment, and tumor progression. Neuroreceptors are critical not only in initiating and advancing cancer but also in conferring resistance to treatments. Neuroreceptors also play a key role, with dopamine receptor D2 activation reducing breast tumor growth by 40% in preclinical models, while serotonin signaling has been shown to promote epithelial–mesenchymal transition (EMT), increasing invasiveness. Advances in understanding these biological mechanisms could lead to more cost-effective and less invasive therapeutic strategies to treat tumors. This review explores the expanding evidence connecting bioelectric activity to breast cancer, focusing on neuroreceptor pharmacology as a transformative therapeutic approach. Examining the modulation of bioelectricity through neuroreceptor pharmacology to influence breast cancer progression and integrating these insights into therapeutic development offers a promising path for addressing treatment challenges and improving precision in managing aggressive cancer subtypes. Full article

Triple-negative breast cancer (TNBC) is an aggressive tumor among breast cancer subtypes with much lower overall survival at metastasis compared to other subtypes and with limited treatment options due to a lack of targeted therapies. This has led to the investigation of molecular targets to advance the development of novel therapeutic agents aimed at treating TNBC patients. Recent studies have led us to believe that glucocorticoid receptor (GR) expression may be predictive of decreased survival and increased risk of metastasis in TNBC tumors. Thus, a detailed understanding of GR signaling in TNBC may help understand the role of GR in TNBC proliferation as well as its role as a potential biomarker and therapeutic target. Recent research findings indicate that GR-induced gene regulations may provide an important platform for the development of GR-based therapeutic targets in TNBC. Emerging data from laboratories indicate that targeting GR has the potential to inhibit cancer cell proliferation and reduce tumor growth in TNBC. Therefore, future research focused on underlying molecular mechanisms of GR action in TNBC could lead to a new effective treatment option for TNBC patients, which is urgently needed. Full article

Background/Objectives: Alzheimer’s disease (AD) severely hinders cognitive function in the hippocampus (HP) and subiculum (SUB), impacting the expression of nicotinic acetylcholine receptors (nAChRs) such as the α7-subtype. To investigate α7 nAChRs as a potential PET imaging biomarker, we report the quantitative binding of [¹²⁵I]α-Bungarotoxin ([¹²⁵I]α-Bgtx) for binding to postmortem human AD (n = 29; 13 males, 16 females) HP compared to cognitively normal (CN) (n = 28; 13 male, 15 female) HP. Methods: For comparisons with common AD biomarkers, adjacent slices were anti-Aβ and anti-Tau immunostained for analysis using QuPath. Results: The [¹²⁵I]α-Bgtx average SUB/HP ratio was 0.5 among the CN subjects, suggesting higher [¹²⁵I]α-Bgtx binding in the HP gray matter regions. The AD subjects showed overall less binding than the CN subjects, with no statistical significance. A positive correlation was found in the [¹²⁵I]α-Bgtx binding in the AD subjects as the age increased. The Braak stage comparisons of [¹²⁵I]α-Bgtx were made with [¹⁸F]flotaza binding to Aβ plaques and [¹²⁵I]IPPI binding to Tau. A positive correlation was found between [¹²⁵I]α-Bgtx and [¹⁸F]flotaza and there was a negative correlation between [¹²⁵I]α-Bgtx and [¹²⁵I]IPPI, implicating intricate relationships between the different AD biomarkers. Conclusions: [¹²⁵I]α-Bgtx shows complimentary potential as a α7 nAChR imaging agent but needs more preclinical assessments to confirm effectiveness for translational PET studies using α7 nAChR radioligands. Full article

Background: Detecting intracellular diffusion dynamics with high spatiotemporal resolution is critical for understanding the complex molecular mechanisms that govern viral infection, drug delivery, and sustained receptor signaling within cellular compartments. Although considerable progress has been made, accurately distinguishing between different types of diffusion in three dimensions remains a significant challenge. Methods: This study extends a previously established two-dimensional, machine learning-based diffusional fingerprinting approach into a three-dimensional framework to overcome this limitation. It presents an algorithm that predicts intracellular motion types based on a comprehensive feature set, including custom statistical descriptors and standard Imaris-derived trajectory features, which capture subtle variations in individual trajectories. The approach employs an extended gradient-boosted decision trees classifier trained on an array of synthetic trajectories designed to simulate diffusion behaviors typical of intracellular environments. Results: The machine learning classifier demonstrated a classification accuracy of over 90% on synthetic datasets, effectively capturing and distinguishing complex diffusion patterns. Subsequent validation using an experimental dataset confirmed the robustness of the approach. The incorporation of the Imaris track features streamlined diffusion classification and enhanced adaptability across diverse volumetric imaging modalities. Conclusions: This work advances our ability to classify intracellular diffusion dynamics in three dimensions and provides a method that is well-suited for high-resolution analysis of intracellular receptor trafficking, intracellular transport of pathogenic agents, and drug delivery mechanisms. Full article

The body’s physiology during physical injuries and diseases depends heavily on the function of acute inflammation. On the other hand, many variables, including iatrogenic, immune system deficiencies, lifestyle, and social and environmental factors, are significant in developing systemic chronic inflammation (SCI). SCI is a major contributor to many diseases and a global cause of death and disability. Therefore, in the present article, we suggest integrative strategies for preventing SCI by addressing receptor overexpression and promoting health improvement. With the objective of reducing chronic inflammation by regulating cytokines, chemokines, and receptor modulation to try to reduce the risk of developing systemic chronic inflammatory diseases (also known as chronic-degenerative diseases, such as diabetes mellitus, cancer, cardiovascular disease, stroke, chronic kidney disease, neurodegenerative disorders, autoimmune diseases, and psychiatric disorders), the strategies we suggest are dietary modifications, exercise, and meditation. Accordingly, the prevention of SCI can be approached holistically with the help of the previous strategies, which may substantially impact public health. Full article

The retinal network relies on glutamate, the primary excitatory neurotransmitter involved in the visual cycle. Glutamate transactions are carried out by an array of distinct receptors and transporters distributed across both pre- and post-synaptic neurons and Müller radial glial cells. Glutamate receptors are broadly divided into two types: ionotropic and metabotropic receptors that differ in their molecular architecture and signaling properties. Within the retina, Müller glia cells span across its entire layers and possess specialized features that enable them to regulate glutamate extracellular levels and thus, its neuronal availability. In order to prevent an excitotoxic insult, retina extracellular glutamate levels have to be tightly regulated through uptake, predominantly into Müller glial cells, by a family of Na⁺-dependent glutamate transporters known as excitatory amino acid transporters. An exquisite interplay between glutamate receptor signaling and glutamate transporter expression and function is fundamental for the integrity and proper function of the retina. This review examines our current understanding of the impact of Müller glial glutamate signaling on glia/neuronal coupling. Full article

Background: External guide sequences (EGSs) are small RNA molecules capable of hybridizing to a target mRNA and rendering the target RNA susceptible to degradation by ribonuclease P (RNase P), a tRNA processing enzyme. Methods: In this study, natural tRNA-originated and engineered variant EGSs were constructed to target the mRNA encoding human CC-chemokine receptor 5 (CCR5), an HIV co-receptor. Results: The EGS variant was about 100-fold more efficient in inducing RNase P-mediated cleavage of the CCR5 mRNA sequence in vitro than a natural tRNA-derived EGS. Furthermore, the expressed variant and natural tRNA-originated EGSs decreased CCR5 expression by 98% and 73–77% and reduced infection by the CCR5-tropic HIV_Ba-L strain in cells by more than 900- and 50-fold, respectively. By contrast, cells expressing these EGSs exhibited no change in the expression of CXCR4, another HIV co-receptor, and showed no reduction in infection by the CXCR4-tropic HIV_IIIB strain, which uses CXCR4 instead of CCR5 as the co-receptor. Thus, the EGSs specifically targeted CCR5 but not CXCR4. Conclusions: Our results demonstrate that EGSs are effective and specific in diminishing HIV infection and represent a novel class of gene-targeting agents for anti-HIV therapy. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including dulaglutide, liraglutide, semaglutide, and exenatide, are effective treatments for type 2 diabetes mellitus (T2DM) and obesity. These agents mimic the action of the endogenous incretin glucagon-like peptide-1 (GLP-1) by enhancing insulin secretion, inhibiting glucagon release, and promoting weight loss through appetite suppression. GLP-1RAs have recently been suggested to have neuroprotective effects, suggesting their potential as treatment for neurodegenerative disorders, such as Alzheimer’s disease (AD). AD and T2DM share several common pathophysiological mechanisms, including insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction. These shared mechanisms suggest that therapeutic agents targeting metabolic dysfunction may also be beneficial for neurodegenerative conditions. Preclinical studies on GLP-1RAs in AD models, both in vitro and in vivo, have demonstrated promising neuroprotective effects, including reductions in amyloid-beta accumulation, decreased tau hyperphosphorylation, improved synaptic plasticity, and enhanced neuronal survival. Despite the encouraging results from preclinical models, several challenges need to be addressed before GLP-1RAs can be widely used for AD treatment. Ongoing clinical trials are investigating the potential cognitive benefits of GLP-1RAs in AD patients, aiming to establish their role as a therapeutic option for AD. This review aimed to examine the current literature on preclinical and clinical studies investigating GLP-1 receptor agonists as potential therapeutic agents for AD. Full article

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