Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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Molecular basis for N-type voltage-gated Ca2+ channel modulation by Gq protein-coupled receptors
Get PDFN-type voltage-gated Ca2+ (CaV2.2) channels, which enable synaptic transmission by triggering neurotransmitter release, are tightly modulated by G protein-coupled receptors (GPCRs) via several downstream signaling messengers, such as Gbg, calmodulin, arachidonic acid and PIP2. However, the molecular mechanism by which Gq/11-coupled receptors (GqPCRs) suppress CaV2.2 currents remains unclear. In this research highlight, we review our recent finding that M1 muscarinic receptors inhibit CaV2.2 channels through both Gbg-mediated voltage-dependent (VD) and G?q/11/PLC-mediated voltage-independent (VI) pathways. Our photometry results also demonstrate that Gbg-mediated VD inhibition of CaV2.2 channels initiates approximately 3s earlier than VI inhibition, and is strongly potentiated in cells expressing plasma membrane-localized CaV b subunits. Our observations demonstrate a novel mechanism for CaV2.2 channel modulation by GqPCRs where the subcellular location of CaV b subunits plays a critical role in determining the voltage-dependence of current suppression by M1 receptors
Estrogen pathway mutations and cancer
Get PDFCancer is caused by an accumulation of mutations in a stem cell. A defective mismatch repair (MMR) system can lead to such an accumulation of mutations. MMR defects are found in a cancer syndrome called Lynch Syndrome, and tumors of this syndrome are indeed characterized by such an accumulation of mutations, particularly in short repetitive DNA sequences, called microsatellites. When such mutated microsatellites are located in the coding sequences of genes with essential roles for tumorigenesis, we speak of ‘target genes’. Many such target genes have been found and in this review we focus the possible involvement of target genes involved in the estrogen-receptor pathway (ER). We recently identified NRIP1, encoding the nuclear receptor-interacting protein 1, as the most frequently mutated gene in microsatellite instable (MSI) endometrial cancer (EC). NRIP1 is a known corepressor of the ER pathway, the pathway essential in regulating the concentrations of estrogens, a hormone for which the endometrium is highly responsive. This in combination with the fact that high exposure to estrogens is currently considered the major risk factor for EC - approximately 80% of all sporadic EC tumors are estrogen dependent carcinomas - make NRIP1 the perfect target gene for EC. Interestingly, mutations in NRIP1 were also detected in MSI colorectal carcinoma (CRC) samples. Finding mutations in an estrogen receptor signaling protein in colorectal tissue might not be that expected, as colon is not typically associated with being responsive to estrogens. However, evidence is accumulating to better understand this finding. For instance, it was shown that NRIP1, in colon tissue, stimulates APC gene transcription and inhibits ?-catenin activation. Moreover, some studies suggested that estrogens can increase the expression of MLH1 in colon cancer cells, highlighting the implications of estrogen protecting against colon cancer, by regulating the MMR system. All in all we conclude that genes involved in the estrogen pathway are the perfect candidates to be studied in MMR-deficient tumors, especially those developing in hormonal responsive tissues
The dual role of androgen receptor in mesenchymal cells
Get PDFThe androgen receptor (AR) mediates differentiation, proliferation and transformation of target tissues. These processes require a crosstalk between epithelial and stromal cells. Prostate cancer (PCa) represents a major cause of cancer-related mortality in men, and is often associated with deregulation of androgen/AR axis. Clinical and molecular findings have highlighted the role of epithelial AR in PCa progression. In contrast, the functions of AR in mesenchymal cells are still unclear. We previously reported that low androgen concentration (1 pM) triggers interaction of AR with the Src tyrosine kinase and PI3-K, thus driving cell cycle progression in fibroblasts. In contrast, stimulation of fibroblasts and fibrosarcoma cells with physiological (10 nM) androgen concentration leads to interaction of AR with full-length filamin A (FLNa) and does not trigger DNA synthesis. On the basis of these findings, we re-examined the role of androgen/AR axis in fibroblasts and human fibrosarcoma HT1080 cells. Recently, we obtained two original and integrated findings on the decision of mesenchymal cells to undergo reversible quiescence and migrate upon stimulation with 10 nM androgens (Castoria et al. 2011 and 2014). This decision is dependent upon the interaction of AR with FLNa. Once assembled, the bipartite AR/FLNa complex recruits a1-integrin and triggers Rac1 activation, thereby enhancing on the one hand cell motility. On the other, Rac 1 activation triggers its downstream effector DYRK 1B, which phosphorylates Ser10 of p27. Stabilization of p27 and cell quiescence then follow. These results strengthen and extend our studies, adding a new and exciting piece to the complex puzzle of signaling networks activated by androgens in target cells. Our findings might have implications for current approaches to AR-related diseases
Transferrin, a Cell Pilot and Iron Provider Based on its Interaction with the Overexpressed Transferrin Receptors
Get PDFTransferrin (Tf) is the serum protein responsible for delivering iron to the erythron and peripheral tissues. Transferrin receptor (TfR), a key receptor in the regulation of iron and is activated by the ferric ion loaded Tf, is overexpressed on the surface of various cancer cells due to their malignant transformation. Based on the Tf-TfR transport mechanism, Tf has been projected to be dually used as a pilot for nanoparticles to target the tumor cells with over expressed TfRs and an intracellular iron provider. Dihydroartemisinin (DHA) is believed a promising tumor therapeutic agent for its unique mechanism of cytotoxicity. When DHA chemically damaging cells, ferrous ions are required to react with the drug. In this research highlight, we discuss our latest published findings which demonstrate the enhanced cytotoxicity of DHA helped with a nanographene oxide carrier and the Tf-TfR transport system, and the potential for its anti-tumor application. This approach gives a further understanding on the role of ligand and receptor in tumor treatments
Soluble urokinase-type plasminogen activator receptor (suPAR) in multiple respiratory diseases
Get PDFSerum soluble urokinase-type plasminogen activator receptor (suPAR) is a glycoprotein secreted during infections and inflammation [1]. Urokinase-type plasminogen activator (uPA) is secreted by polymorphonuclear neutrophils (PMN) and macrophages; then uPA binds to membrane urokinase-type plasminogen activator receptor (uPAR) [2]. suPAR is formed by cleaved from the uPAR [2]. suPAR is expressed in various cell types, such as macrophages monocytes, endothelial cells and neutrophils [3]. suPAR can be potentially cause or modulate various diseases in patients with cancer, various infectious and inflammatory diseases (including infections with human immunodeficiency virus (HIV), tuberculosis, liver fibrosis and inflammatory bowel disease) [2, 3]. suPAR can convert plasminogen to plasmin, which degrades fibrin, activates matrix metalloproteases and mediates proteolysis of extracellular matrix proteins during cellular invasion [4]. suPAR modulate the functions of integrins (including activating intracellular signals, monocyte chemotaxis, cell adhesion and proliferation) [4, 5]. So suPAR contributes to cell adhesion, migration, proliferation inflammation, chemotaxis, proteolysis, immune system activation, tissue remodeling and signal transduction [5, 6]. Several studies have identified that suPAR level is a important marker in patients with various diseases and associated with a poorer outcome in a range of non-infectious and infectious diseases [2]. Biomarkers of lung disease are required to aid diagnosis, define clinical phenotypes and monitor the response to existing and new therapeutic strategies. Our review aims to explore the potential of suPAR as a general marker in the diagnosis, prognosis and follow-up of therapy of lung disease
Androgen Receptor (AR) and Breast Cancer: Reference to the AR Status in Normal/Benign Breast Luminal Cells
Get PDFThe role of androgen and androgen receptor pathway in breast cancer development, prognosis and treatment has gained enormous attentions in recent years, largely because of the effort to identify new markers for targeted treatment of triple (ER/PR/Her2) negative breast carcinomas. This mini-review will discuss AR and breast cancer from the perspectives of normal/benign breast luminal epithelium
Mechanism of Deltamethrin induced Immunotoxicity: Current and Future Perspectives
Get PDFThe immune system is the most vulnerable system regarding toxicity of pesticides. Any alteration in the immune functions makes an individual immunocompromised and more susceptible to cancer, infections, autoimmunity and allergies. Deltamethrin is the most popular type 2 pyrethroid insecticide which is widely use in agriculture and home due to restriction on the organophosphate insecticides. Due to their extensive use, it becomes an increasingly serious source of chemical pollution. We all are exposed to deltamethrin through inhalation, ingestion and dermal contact. It has been demonstrated that deltamethrin alters the immune response signalling pathways, but its mechanism of immunotoxicity is still an open question for researchers to be explored. Thus, herein we tried to understand the mechanism of deltamethrin induced immunotoxicity. Possibilities of deltamethrin induced other immunotoxic signalling pathways have also been discussed and should be considered in future studies. Further, current challenges and future perspectives have been also discussed
Receptor research on xenohormone effects of human serum extracts containing the actual mixture of perfluorinated alkyl acids: a short review
Get PDFPerfluorinated alkyl acids (PFAAs) are used in many household products including food contact materials. Hence, humans are continuously exposed, and the PFAAs are accumulated in human serum with half-lives up to 8.8 years. In humans, high PFAA serum levels have been associated with an increased risk of breast cancer and other adverse health effects such as lower birth weight and longer time to pregnancy which might be related to disruptions of various hormonal systems. For instance, direct cell exposure studies in vitro suggest that some PFAAs can transactivate the estrogen receptor (ER), antagonize the androgen receptor (AR) and has the potential to interfere with TH and AhR functions. Moreover, the PFAAs also showed cellular oxidative stress.
Humans are exposed to an array of PFAAs, and the quantity and combination of these PFAAs in human serum differs between individuals. Hence, the toxicological studies of single PFAAs and simple mixtures might be insufficient to predict how the actual mixtures of PFAAs may affect humans. To get a better evaluation of the actual mixture effects, we developed a method to extract the actual mixture of PFAAs from human serum. Preliminary results showed that 17% of the PFAA serum fractions from pregnant women could significantly transactivate the ER, and 94% of the fractions could further increase the transactivity induced by the potent ER ligand 25 pM 17?-estradiol. As part of the international FETOTOX project (http://fetotox.au.dk/), we are currently extracting the actual PFAA serum mixture from 700 pregnant women to further elucidate whether the serum PFAA mixture can transactivate the ER at the levels found in human serum. We suggest that our method can in the future be used to study the actual serum PFAA mixture effects on both steroid hormone actions as well as other hormonal systems e.g. thyroid hormone function. In the current review we will discuss how our recently developed PFAA extraction method might be used in future research to assess the endocrine impact of PFAAs on human health
Liver X receptors connect nuclear O-GlcNAc signaling to hepatic glucose utilization and lipogenesis
Get PDFInsulin is a central regulator of glycolysis and de novo lipogenesis in the liver. However, hepatic glucose metabolism has been shown to activate the transcription of glycolytic and lipogenenic enzymes independently of insulin. The nuclear liver X receptors LXRa and LXRb play a major role in glucose and lipid metabolism, regulating transcription of glycolytic and lipogenic enzymes in liver, which is believed to be mediated by oxysterol ligand activation and insulin signaling. The majority of hepatic glucose-responsive genes are regulated by carbohydrate response element-binding protein (ChREBP), a transcriptional regulator that requires glucose metabolism via the hexosamine biosynthetic pathway and O-GlcNAc transferase (OGT)-mediated O-GlcNAc modification for full activation. We have previously shown that also LXRs are targets for O-GlcNAc modification in response to glucose and refeeding, promoting lipogenic gene expression. We recently addressed the relative roles of insulin, glucose and LXR in regulating hepatic glycolytic and lipogenic gene expression in vivo by subjecting untreated control and streptozotocin (STZ)-treated LXRa/b+/+ and LXRa/b-/- mice to a fasting-refeeding regime. STZ was used to destroy pancreatic ?-cells and insulin production. We found that under hyperglycemic and hypoinsulinemic conditions, LXRs maintained their ability to upregulate the expression of glycolytic and lipogenic enzymes, including glucokinase (GK), sterol regulatory element-binding protein (SREBP-1c), ChREBPa and the newly identified shorter isoform ChREBPb. ChREBPa expression became dependent on LXR under hyperglycemic and hypoinsulinemic conditions, which was mediated, at least in part, by OGT signaling. Moreover, we found that LXR and OGT interacted and co-localized in the nucleus in Huh7 cells and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling, ChREBP O-GlcNAcylation and activity in vivo. We propose that LXR regulation of nuclear O-GlcNAc signaling and ChREBP O-GlcNAcylation is part of a mechanism linking hepatic glucose utilization with lipid synthesis
Chemokine receptors and their interactors in HIV-1 replication: potential therapeutic targets
Get PDFChemokine receptors CXCR4 and CCR5 are co-receptors indispensable for human immunodeficiency virus type 1 (HIV-1) entry and subsequent infection in host cells. Antiretroviral therapies based on the viral proteins have been developed, and significant achievements have been made in the treatment of HIV/AIDS patients based on the HAART regimens. However, a lot of concerns are still present, the purge of latent viral reservoirs and cure of AIDS are currently impossible, and prophylactic vaccines are not yet available. Most recently, HIV-1 entry has been understood much more and targeting viral entry based on chemokine receptors represents an interesting prospective. In this research highlight, we review the role of HIV-1 co-receptors-interacting proteins during chemokine receptor signal activation and assembly, as well as present new results about how they can regulate the replication of the virus