Receptors

Neuroendocrine tumors (NETs) represent a diverse group of neoplasms originating from neuroendocrine cells, presenting varied clinical behaviors and posing significant challenges in management. This review explores the emerging roles of receptor tyrosine kinases (RTKs) in the pathogenesis and progression of NETs, including vascular endothelial growth factor receptors (VEGFRs), insulin-like growth factor receptors (IGF-1R), RET, epidermal growth factor receptor (EGFR), and ALK. The dysregulation of RTK signaling pathways contributes to key cellular processes such as proliferation, survival, and invasion in NETs. We discuss the potential of targeting RTKs as therapeutic strategies in NETs, with a focus on recent developments in RET inhibitors and the therapeutic implications of RTK alterations. Full article

Recent research has emphasized the potential of natural and synthetic cannabinoids as anticancer agents. Yet it remains unclear whether and in which sense cannabinoids affect the anticancer activity of NK cells, an important branch of anticancer immunity. Similar uncertainty exists regarding NK cells-based immunotherapy. Here we presented an overview of multiple cannabinoid targets as canonical (mainly CB2) and non-canonical receptors, ion channels, transporters, and enzymes, expressed in NK cells, along with underlying molecular mechanisms. Through them, cannabinoids can affect viability, proliferation, migration, cytokine production, and the overall anticancer activity of NK cells. Respective holistic studies are limited, and, mostly, are phenomenological, not linking observed effects with certain molecular targets. Another problem of existing studies is the lack of standardisation, so that diverse cannabinoids at variable concentrations and ways of administration are applied, and often, instead of purified NK cells, the whole lymphocyte population is used. Therefore, there is an urgent need for more focused, systemic, and in-depth studies of the impact of the cannabinoid toolkit on NK cell function, to critically address the compatibility and potential synergies between NK activity and cannabinoid utilization in the realm of anticancer interventions. Full article

Receptology, the science of receptors, is a multidimensional field of research which can be dissected into biosynthesis, membrane sorting, ligand binding and signal transduction. Plasma membrane receptors connect the cells with their environment and transmit signals that are translated into biological information. The historical paradigm of ligand–receptor interactions is the lock-and-key model. This model presupposes that both partners have a precise 3D shape that perfectly fits together to form the ligand–receptor complex. However, this simple model suffers from severe limitations due to several levels of simplifications: (i) water molecules and membrane lipids are not considered; (ii) not all ligands have a stable 3D structure; (iii) the ligand-binding pocket of the receptor is often flexible and conformationally rearranged after the initial binding step (induced fit mechanism) and/or subjected to conformational selection by the ligand; (iv) there are signal transduction mechanisms which can be either purely mechanical (conformational change of the receptor induced after binding of the ligand), lipid-assisted (e.g., by raft lipids such as cholesterol or gangliosides), or in some instances of quantic nature (detection of odorant molecules). The aim of the present review is to challenge the old paradigms and present new concepts of membrane receptology that consider the impact of critical parameters such as water molecules, membrane lipids, electrostatic surface potential and quantum mechanisms. Full article

The development of potent BRAF inhibitors has revolutionized the treatment of BRAF mutant cancers, in particular, melanomas. However, BRAF mutant cancers of other entities, e.g., colorectal cancers, display distinctly reduced responses to BRAF inhibitors. In addition, the emergence of cancer resistance to BRAF inhibitor treatment poses a severe problem. The reactivation of MAPK/ERK signaling was identified as an important mode of BRAF inhibitor resistance. Receptor tyrosine kinases (RTKs), which are prominent anticancer drug targets in their own right, play a crucial role in the development of drug resistance to BRAF inhibitors and the reactivation of MAPK/ERK signal transduction, as well as the establishment of bypassing signaling pathways. MAPK reactivation can occur via increased expression of RTKs, altered RTK signaling, and post-translational processes, among others. This review summarizes the influence of pertinent RTKs on BRAF mutant cancers and BRAF inhibitor resistance and outlines possible and proven ways to circumvent BRAF-associated resistance mechanisms. Full article

The involvement of the prefrontal cortical dopaminergic system in the psychopathology of epilepsies and comorbid conditions such as autism spectrum disorder (ASD) still needs to be explored. We used autoradiography to study the D1-like (D1DR) and D2-like (D2DR) receptor binding density in the prefrontal cortex of normal Wistar rats and Wistar-derived strains with generalized convulsive and/or non-convulsive epilepsy. WAG/Rij rats served as a model for non-convulsive absence epilepsy, WAG/Rij-AGS as a model of mixed convulsive/non-convulsive form, and KM strain was a model for convulsive epilepsy comorbid with an ASD-like behavioral phenotype. The prefrontal cortex of rats with any epileptic pathology studied demonstrated profound decreases in binding densities to both D1DR and D2DR; the effects were localized in the primary and secondary anterior cingulate cortices, and adjacent regions. The local decreased D1DR and D2DR binding densities were independent of (not correlated with) each other. The particular group of epileptic rats with an ASD-like phenotype (KM strain) displayed changes in the lateral prefrontal cortex: D1DR were lowered, whereas D2DR were elevated, in the dysgranular insular cortex and adjacent regions. Thus, epilepsy-related changes in the dopaminergic system of the rat archeocortex were localized in the medial prefrontal regions, whereas ASD-related changes were seen in the lateral prefrontal aspects. The findings point to putative local dopaminergic dysfunctions, associated with generalized epilepsies and/or ASD. Full article

Almost exactly 35 years after starting to work with the human glucocorticoid receptor (hGR), it is interesting for me to re-evaluate the data and results obtained in the 1980s–1990s with the benefit of current knowledge. What was understood then and how can modern perspectives increase that understanding? The hGR’s tau1c activation domain that we delineated was an enigmatic protein domain. It was apparently devoid of secondary and tertiary protein structures but nonetheless maintained gene activation activity in the absence of other hGR domains, not only in human cells but also in yeast, which is evolutionarily very divergent from humans and which does not contain hGR or other nuclear receptors. We now know that the basic machinery of cells is much more conserved across evolution than was previously thought, so the hGR’s tau1c domain was able to utilise transcription machinery components that were conserved between humans and yeast. Further, we can now see that structure–function aspects of the tau1c domain conform to a general mechanistic framework, such as the acidic exposure model, that has been proposed for many activation domains. As for many transcription factor activation domains, it is now clear that tau1c activity requires regions of transient secondary structure. We now know that there is a tendency for positive Darwinian selection to target intrinsically disordered protein domains. It will be interesting to study the distribution and nature of the many single nucleotide variants of the hGR in this respect. Full article

That signaling bias is a n^th level of complexity in the understanding of G protein-coupled receptor (GPCR) activation is a first fact. That its exhaustive description, including the mode d’emploi of its quantitative measurement, remains a challenge is a second fact. That the use of this concept is promising for the design of drug candidates is a third fact. That the translation of signaling biases observed into in vivo specific effects is well documented is a fourth fact. However, the road to apply those aspects of receptology to a systematic description of a ligand and, a fortiori, of a drug candidate, still necessitates a huge body of studies. In the present commentary, the merits of the molecular description of receptor bias signaling are highlighted and the ligand induced-fit impact on GPCR structure, as well as on the functional repertoire of GPCRs, is discussed. An emphasis is given to the practical aspects during drug design, and, thus, the practical limitations of the current approaches, particularly in the context of as soon as the data are transferred to more integrated/living systems, might be a major limitation. Full article

Major depression is related to dysfunction of the GABAergic pathway. Interestingly, the antidepressant fluoxetine modifies GABAergic neurotransmission in human and animal models of depression. However, the effects of norfluoxetine (the main metabolite of fluoxetine) on GABAergic neurotransmission have not yet been studied. Therefore, we explored whether fluoxetine and/or norfluoxetine may regulate GABAergic transmission and whether these substances interact with GABA_A receptors in hippocampal CA1 stratum radiatum interneurons. For these purposes, we recorded the firing profile, GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs), and currents induced by GABA puffs in stratum radiatum interneurons using both whole-cell current- and voltage-clamp techniques. Interneurons were selected according with their high firing profile. We found that both fluoxetine and norfluoxetine (at 20 µM) significantly decreased the frequency of sIPSCs without modifying their amplitude and decreased the amplitude of GABA-induced currents. These results indicate that fluoxetine and norfluoxetine decrease GABA release from neurons contacting stratum radiatum interneurons and negatively modulate GABA_A receptors in these interneurons, resulting in their disinhibition, which in turn may contribute to increasing the inhibition of hippocampal CA1 pyramidal neurons. Full article

Orphan nuclear receptor subfamily 4A (NR4A) are key regulators of inflammatory responses, largely by their interactions with NF-κB. Over the last decade, several NR4A modulators have been developed, and they are showing potential as therapeutics, although their widespread use in laboratory settings is limited. Here, we have examined, using myeloid cell line THP-1, whether the NR4A modulator 3-[(4-Chlorophenyl)-(1H-indol-3-yl)methyl]-1H-indole (C-DIM12) can alter the inflammatory outcome of six inflammatory ligands: lipopolysaccharide (LPS), tumour necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), flagellin (FL), lipoteichoic acid (LTA), and zymosan (ZY). We demonstrate that C-DIM12 (10 µM) selectively alters the secretion of inflammatory chemokine MCP-1 following exposure to distinct inflammatory ligands in a concentration-dependent manner. Furthermore, data obtained from THP-1 Lucia cell experiments show that 10 µM C-DIM12, and not 1 µM C-DIM12, can significantly attenuate the increased NF-κB transcriptional activity observed following the exposure to several inflammatory ligands (LPS, FL, TNFα, LTA, and ZY). Lastly, experimental analysis confirms that the cellular action(s) of C-DIM12 is independent of changes in metabolic parameters. Thus, these data contribute to the understanding of how the NR4A modulator C-DIM12 alters inflammatory responses in a myeloid cell following exposure to multiple ligands. Full article

Taste 2 receptors (T2Rs) are G-protein-coupled receptors responsible for sensing bitter tastes. Many studies have shown the expression of T2Rs in extraoral tissues and the unique role of T2Rs in each tissue. Single-nucleotide polymorphisms of T2Rs are associated with the risk of obesity and diabetes, and the organs/tissues associated with the development of these metabolic diseases, including the intestine, adipose, muscle, liver, and pancreas, are reported to express T2R genes. This result suggests that T2Rs in extraoral tissues contribute to the development of obesity and diabetes. In this narrative review, we summarize current knowledge of the associations of T2Rs with obesity and diabetes, provide an overview of extraoral tissues that are associated with the development of obesity and diabetes that express T2R genes, and summarize the current knowledge of T2Rs. Full article

Neuroinflammation is considered to be a significant component in a range of neuropathologies. Unfortunately, whilst its role is well recognised, the options for therapeutic intervention are limited. As such, there is a need to identify novel targets in order to increase treatment options. Given its role as both a neurotransmitter and an immune modulator, substance P (SP) and its NK1 receptor (NK1R) have been widely studied as a potential therapeutic target. There is evidence that NK1R antagonists may exert beneficial effects in a range of conditions, including traumatic brain injury and stroke. Blocking the NK1R has been shown to reduce blood–brain barrier dysfunction, reduce cerebral oedema, and reduce the levels of pro-inflammatory cytokines. These actions are associated with improved survival and functional outcomes. The NK1R has also been shown to be involved in the inflammatory reaction to CNS infection, and hence antagonists may have some benefit in reducing infection-driven inflammation. However, the NK1R may also play a role in the host immune response to infection, and so here, the potential beneficial and detrimental effects need to be carefully balanced. The purpose of this review is to provide a summary of evidence for the involvement of the NK1R in acute CNS inflammation, particularly in the context of traumatic brain injury and stroke. Full article

Binding of substance P to the tachykinin NK1 receptor is involved in numerous physiological and pathophysiological processes ranging from modulation of sensory and motor function to inflammation, cancer, and brain injury, amongst others. NK1 antagonists therefore have enormous potential as a therapeutic intervention in a wide variety of human disease states, albeit that the clinical potential is yet to be fully realised. In the current review, the role of substance P in the pathophysiology of traumatic brain injury (TBI) will be discussed, summarising both experimental and clinical observations in mild, moderate, and severe TBI. In addition, the potential for NK1 antagonists to be a valuable therapeutic intervention against chronic traumatic encephalopathy (CTE) after repeated concussive brain injury as well as raised intracranial pressure (ICP) following severe TBI will be addressed, highlighting the various pathophysiological processes that are attenuated by the intervention. Full article

Atherosclerosis is a pathological condition characterized by the accumulation of plaques in the arteries, leading to cardiovascular diseases. The deposition of cholesterol in peripheral cells increases the risk of atherosclerosis. Reverse cholesterol transport (RCT) is essential to reduce the risk of atherosclerosis because it removes excessive cholesterol from the peripheral tissues. ATP-binding cassette transporters such as ABCA1, ABCG1, ABCG5, and ABCG8 are involved in the efflux of cholesterol. The upregulation of these ABC transporters enhances RCT, thereby promoting the removal of excess cholesterol from the body. The expression and activity of ABC transporters are regulated by transcriptional and post-transcriptional mechanisms, as well as by post-translational modifications. In this review, the regulation of ABC transporters by nuclear receptors such as farnesoid X receptor, liver X receptor, retinoid X receptor, retinoic acid receptor, and peroxisome proliferator-activated receptors is discussed. Pharmacological and natural compounds serving as agonists for the nuclear receptors have been identified to elevate the mRNA levels of the transporters. Consequently, it is anticipated that these compounds will attenuate the development of atherosclerosis through stimulation of the ABC transporters, thereby enhancing RCT and fecal cholesterol excretion. Understanding these regulatory processes can aid in the development of therapeutic approaches to prevent atherosclerosis. Full article

The adenosine-5’ triphosphate (ATP)-gated, ion channel, P2X receptor superfamily has seven members expressed by many cancer types. Subtype 7 (P2X7 receptor) is expressed consistently at levels higher than in comparatively healthy tissues. Moreover, transcript variant heterogeneity is associated with drug resistance. We have previously described the role of the P2X7 receptor in myeloma, a rare blood disease that uniquely presents with aggressive bone destruction. In this study, we used known agonists of the P2X7 receptor to induce calcium influx and YO-PRO-1 uptake in murine MOPC315.BM myeloma cells as readouts of P2X7 receptor-mediated channel activation and pore formation, respectively. Neither ATP- nor BzATP-induced calcium influx and YO-PRO-1 indicated an absence of the P2X7 receptor function on MOPC315.BM cells. TaqMan revealed low (Ct > 35) P2rx7 but high P2rx4 gene expression in MOPC315.BM; the latter was downregulated with BzATP treatment. The concomitant downregulation of CD39/Entpd1, Icam-1, and Nf-kb1 and the upregulation of Casp-1 genes regulated during purinergic signaling and with established roles in myeloma progression suggest P2RX4-mediated survival adaptation by cancer cells. Further studies are needed to characterize the P2RX4 pharmacology on MOPC315.BM since transcriptional regulation may be utilized by cancer cells to overcome the otherwise toxic effects of high extracellular ATP. Full article

Estrogen receptor beta 1 (ERβ1) is a ligand-activated nuclear receptor, which has been shown to maintain tissue differentiation in the normal prostate, and regulate androgen response and increase expression of tumor suppressors in prostate cancer cell lines. There are three shorter isoforms of ERβ expressed in the human prostate, ERβ2, ERβ4, and ERβ5, which have already been implicated in chemotherapy resistance and disease progression, suggesting a possible oncogenic role. Their ligand-binding domain (LBD) is truncated, so they are unable to activate canonical ERβ1 signaling pathways; however, they were shown to participate in hypoxic signaling and to induce a gene expression signature associated with stemness and hypoxia. To elucidate the role of the truncated ERβ isoforms in prostate cancer, we created a knockout of all isoforms, as well as a truncation of the LBD, to remove the function of ERβ1. We showed that the removal of all isoforms leads to a decrease in the expression of cancer stem cell (CSC)-associated genes, decreased chemotherapy resistance, and a decrease in the CSC population, based on sphere formation ability and SORE6 (CSC reporter) activity, while removing the LBD function only had the opposite effect. Our results suggest a more aggressive phenotype in prostate cancer cell lines expressing ERβ variants. Full article

The steroid/thyroid hormone or nuclear receptor superfamily is quickly approaching its 40th anniversary. During this period, we have seen tremendous progress being made in our understanding of the mechanisms of action of these physiologically important proteins in the field of health and disease. Critical to this has been the insight provided by ever more detailed structural examination of nuclear receptor proteins and the complexes they are responsible for assembling on DNA. In this article, I will focus on the contributions made by Jan-Åke Gustafsson and colleagues at the Karolinska Institute (Sweden) and, more recently, the University of Houston (USA), to this area of nuclear receptor research. Full article

The cycle number (n_c) of a recycling receptor is defined as the average number of round trips (cell surface–endosome–cell surface) the receptor can make before it is degraded. This characteristic parameter of recycling receptors can be easily determined from the receptor’s half-life (t_½, the time in which 50% of the receptor is degraded) and cycling time (T_c, the time a receptor needs to complete a round trip). Relationship analyses revealed that n_c increases linearly with increasing t_½ and decreases exponentially with increasing T_c. For commonly observed t_½ and T_c values, it was calculated that recycling receptors have n_c values of <300. In addition, it was found that recycling receptors in cancer cells have generally smaller n_c values (<100), whereas recycling receptors in normal cells have larger n_c values (>100). Based on this latter finding, the cycle number n_c may be a useful criterion for distinguishing between cancer and normal cells. Full article

Communication between cells is essential in maintaining homeostasis. The persistent disruption of cell–cell communication by environmental contaminants contributes to progressive disease and toxicity. In this study, single-nuclei RNA sequencing (snRNAseq) data was used to examine dose-dependent cell-specific changes in cell–cell communication associated with the development of liver pathologies following the persistent activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Published hepatic snRNAseq data from male mice gavaged with sesame-oil vehicle or TCDD every 4 days for 28 days was used to assess the AHR-mediated disruption of ligand–receptor interactions. Analysis identified that portal fibroblasts and liver sinusoidal endothelial cells contributed the most ligand–receptor pairs at doses < 0.3μg/kg TCDD. Doses ≥ 0.3 μg/kg TCDD increased the putative intercellular communication between hepatocytes and hepatic stellate cells. In control livers, interactions primarily consisted of protease-activated receptor (PAR) signaling. TCDD treatment increased the number of active signaling pathways. Within hepatocytes, neuregulin signaling was induced, activating the NRG1–ERBB4 ligand axis, consistent with AHR genomic enrichment at dioxin response elements in a published chromatin immunoprecipitation sequencing (ChIP-seq) dataset, which suggested a direct regulation. Collectively, the results suggest that the disruption of cell signaling may play a central role in TCDD-elicited liver pathologies. Full article

Melatonin, the hormone of darkness, is secreted in minute amounts during the night and is virtually undetectable during the day. Melatonin mainly acts on high-affinity G protein-coupled receptors. The present review will trace the path of the discovery of melatonin receptors from their cloning, expression and purification to the development of recent radioactive and fluorescent tracers. We will then report on the state-of-the-art of melatonin receptor functional properties, including ligand bias and system bias due to receptor-associated proteins and receptor heteromers. Currently available antibodies raised against melatonin receptors will be critically reviewed here for the first time. The review will close with future perspectives in terms of the discovery of allosteric ligands and the in vivo validation of a range of melatonin receptor-associated signaling complexes to improve future drug development. Full article