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1.
To Detach, Migrate, Adhere, and Metastasize: CD97/ADGRE5 in Cancer.
Aust, G, Zheng, L, Quaas, M
Cells. 2022;(9)
Abstract
Tumorigenesis is a multistep process, during which cells acquire a series of mutations that lead to unrestrained cell growth and proliferation, inhibition of cell differentiation, and evasion of cell death. Growing tumors stimulate angiogenesis, providing them with nutrients and oxygen. Ultimately, tumor cells invade the surrounding tissue and metastasize; a process responsible for about 90% of cancer-related deaths. Adhesion G protein-coupled receptors (aGPCRs) modulate the cellular processes closely related to tumor cell biology, such as adhesion and detachment, migration, polarity, and guidance. Soon after first being described, individual human aGPCRs were found to be involved in tumorigenesis. Twenty-five years ago, CD97/ADGRE5 was discovered to be induced in one of the most severe tumors, dedifferentiated anaplastic thyroid carcinoma. After decades of research, the time has come to review our knowledge of the presence and function of CD97 in cancer. In summary, CD97 is obviously induced or altered in many tumor entities; this has been shown consistently in nearly one hundred published studies. However, its high expression at circulating and tumor-infiltrating immune cells renders the systemic targeting of CD97 in tumors difficult.
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Amino Acid-Induced Impairment of Insulin Signaling and Involvement of G-Protein Coupling Receptor.
Zakaria, NF, Hamid, M, Khayat, ME
Nutrients. 2021;(7)
Abstract
Amino acids are needed for general bodily function and well-being. Despite their importance, augmentation in their serum concentration is closely related to metabolic disorder, insulin resistance (IR), or worse, diabetes mellitus. Essential amino acids such as the branched-chain amino acids (BCAAs) have been heavily studied as a plausible biomarker or even a cause of IR. Although there is a long list of benefits, in subjects with abnormal amino acids profiles, some amino acids are correlated with a higher risk of IR. Metabolic dysfunction, upregulation of the mammalian target of the rapamycin (mTOR) pathway, the gut microbiome, 3-hydroxyisobutyrate, inflammation, and the collusion of G-protein coupled receptors (GPCRs) are among the indicators and causes of metabolic disorders generating from amino acids that contribute to IR and the onset of type 2 diabetes mellitus (T2DM). This review summarizes the current understanding of the true involvement of amino acids with IR. Additionally, the involvement of GPCRs in IR will be further discussed in this review.
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G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases.
DeLeon, C, Wang, DQ, Arnatt, CK
Frontiers in endocrinology. 2020;:578536
Abstract
There are gender differences between men and women in many physiological functions and diseases, which indicates that female sex hormones may be important. Traditionally, estrogen exerts its biological activities by activating two classical nuclear estrogen receptors, ESR1 and ESR2. However, the roles of estrogen in the regulation of physiological functions and the pathogenesis of diseases become more complicated with the identification of the G protein-coupled estrogen receptor (GPER1). Although many GPER1-specific ligands have been developed, the therapeutic mechanisms of exclusively targeting GPER1 are not yet well understood. Translational applications and clinical trial efforts for the identified GPER1 ligands have been focused primarily on the reproductive, cardiovascular, nervous, endocrine, and immune systems. More recently, research found that GPER1 may play an important role in regulating the digestive system. Cholesterol gallstone disease, a major biliary disease, has a higher prevalence in women than in men worldwide. Emerging evidence implies that GPER1 could play an important role, independent of the classical ESR1, in the pathophysiology of cholesterol gallstones in women. This review discusses the complex signaling pathways of three estrogen receptors, highlights the development of GPER1-specific ligands, and summarizes the latest advances in the role of GPER1 in the pathogenesis of gallstone formation.
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Expression and Role of the G Protein-Coupled Estrogen Receptor (GPR30/GPER) in the Development and Immune Response in Female Reproductive Cancers.
Hernández-Silva, CD, Villegas-Pineda, JC, Pereira-Suárez, AL
Frontiers in endocrinology. 2020;:544
Abstract
Cancer is a major public health issue and represents the second leading cause of death in women worldwide, as female reproductive-related neoplasms are the main cause of incidence and mortality. Female reproductive cancers have a close relationship to estrogens, the principal female sex steroid hormones. Estrogens exert their actions by the nuclear estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). ERα, and ERβ act as transcription factors mediating genomic effects. Besides, the G protein-coupled estrogen receptor (GPER, formerly known as GPR30) was recently described as a seven-transmembrane receptor that mediates non-genomic estrogenic signaling, including calcium mobilization, cAMP synthesis, cleavage of matrix metalloproteinases, transactivation of epidermal growth factor receptor (EGFR), and the subsequent activation of PI3K and MAPK signaling pathways, which are the reasons why it is related to cellular processes, such as cell-cycle progression, cellular proliferation, differentiation, apoptosis, migration, and invasion. Since its discovery, selective agonists and antagonists have been found and developed. GPER has been implicated in a variety of hormone-responsiveness tumors, such as breast, endometrial, ovarian, cervical, prostate, and testicular cancer as well as lung, hepatic, thyroid, colorectal, and adrenocortical cancers. Nevertheless, GPER actions in cancer are still debatable due to the conflicting information that has been reported to date, since many reports indicate that activation of this receptor can modulate carcinogenesis. In contrast, many others show that its activation inhibits tumor activity. Besides, estrogens play an essential role in the regulation of the immune system, but little information exists about the role of GPER activation on its modulation within cancer context. This review focuses on the role that the stimulation of GPER plays in female reproductive neoplasms, specifically breast, endometrial, ovarian, and cervical cancers, in its tumor activity and immune response regulation.
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5.
The energetics of protein-lipid interactions as viewed by molecular simulations.
Corey, RA, Stansfeld, PJ, Sansom, MSP
Biochemical Society transactions. 2020;(1):25-37
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Abstract
Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Integral, membrane proteins are embedded in this bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is, therefore, important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe many computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular, we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bis-phosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation.
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The expanding roles and mechanisms of G protein-mediated presynaptic inhibition.
Zurawski, Z, Yim, YY, Alford, S, Hamm, HE
The Journal of biological chemistry. 2019;(5):1661-1670
Abstract
Throughout the past five decades, tremendous advancements have been made in our understanding of G protein signaling and presynaptic inhibition, many of which were published in the Journal of Biological Chemistry under the tenure of Herb Tabor as Editor-in-Chief. Here, we identify these critical advances, including the formulation of the ternary complex model of G protein-coupled receptor signaling and the discovery of Gβγ as a critical signaling component of the heterotrimeric G protein, along with the nature of presynaptic inhibition and its physiological role. We provide an overview for the discovery and physiological relevance of the two known Gβγ-mediated mechanisms for presynaptic inhibition: first, the action of Gβγ on voltage-gated calcium channels to inhibit calcium influx to the presynaptic active zone and, second, the direct binding of Gβγ to the SNARE complex to displace synaptotagmin downstream of calcium entry, which has been demonstrated to be important in neurons and secretory cells. These two mechanisms act in tandem with each other in a synergistic manner to provide more complete spatiotemporal control over neurotransmitter release.
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Taste, olfactory and texture related genes and food choices: implications on health status.
Precone, V, Beccari, T, Stuppia, L, Baglivo, M, Paolacci, S, Manara, E, Miggiano, GAD, Falsini, B, Trifirò, A, Zanlari, A, et al
European review for medical and pharmacological sciences. 2019;(3):1305-1321
Abstract
OBJECTIVE The food choices are due to a mixture of sensory signals including gustatory, olfactory, and texture sensations. The aim of this quality review was to update data about studies concerning genetics of taste, olfactory and texture receptors and their influence on the health status in humans. MATERIALS AND METHODS An electronic search was conducted in MEDLINE, Pubmed database and Scopus, for articles published in English until December 2018. Two independent researches selected the studies and extracted the data. RESULTS The review confirms the importance of inter-individual variations in taste, olfactory and texture related genes on food choices and their implications in the susceptibility to nutrition-related conditions such as obesity, dental caries, diabetes, cardiovascular disease, hypertension, hyperlipidemia and cancer. CONCLUSIONS The knowledge of variants in taste, olfactory and texture related genes can contribute to the prevention of diseases related to unhealthy nutrition. Further studies would be useful to identify other variants in the genes involved in these systems.
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Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives.
Barton, M, Filardo, EJ, Lolait, SJ, Thomas, P, Maggiolini, M, Prossnitz, ER
The Journal of steroid biochemistry and molecular biology. 2018;:4-15
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Abstract
Estrogens play a critical role in many aspects of physiology, particularly female reproductive function, but also in pathophysiology, and are associated with protection from numerous diseases in premenopausal women. Steroids and the effects of estrogen have been known for ∼90 years, with the first evidence for a receptor for estrogen presented ∼50 years ago. The original ancestral steroid receptor, extending back into evolution more than 500 million years, was likely an estrogen receptor, whereas G protein-coupled receptors (GPCRs) trace their origins back into history more than one billion years. The classical estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that confer estrogen sensitivity upon many genes. It was soon apparent that these, or novel receptors may also be responsible for the "rapid"/"non-genomic" membrane-associated effects of estrogen. The identification of an orphan GPCR (GPR30, published in 1996) opened a new field of research with the description in 2000 that GPR30 expression is required for rapid estrogen signaling. In 2005-2006, the field was greatly stimulated by two studies that described the binding of estrogen to GPR30-expressing cell membranes, followed by the identification of a GPR30-selective agonist (that lacked binding and activity towards ERα and ERβ). Renamed GPER (G protein-coupled estrogen receptor) by IUPHAR in 2007, the total number of articles in PubMed related to this receptor recently surpassed 1000. In this article, the authors present personal perspectives on how they became involved in the discovery and/or advancement of GPER research. These areas include non-genomic effects on vascular tone, receptor cloning, molecular and cellular biology, signal transduction mechanisms and pharmacology of GPER, highlighting the roles of GPER and GPER-selective compounds in diseases such as obesity, diabetes, and cancer and the obligatory role of GPER in propagating cardiovascular aging, arterial hypertension and heart failure through the stimulation of Nox expression.
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The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease.
Hershfinkel, M
International journal of molecular sciences. 2018;(2)
Abstract
A distinct G-protein coupled receptor that senses changes in extracellular Zn2+, ZnR/GPR39, was found in cells from tissues in which Zn2+ plays a physiological role. Most prominently, ZnR/GPR39 activity was described in prostate cancer, skin keratinocytes, and colon epithelial cells, where zinc is essential for cell growth, wound closure, and barrier formation. ZnR/GPR39 activity was also described in neurons that are postsynaptic to vesicular Zn2+ release. Activation of ZnR/GPR39 triggers Gαq-dependent signaling and subsequent cellular pathways associated with cell growth and survival. Furthermore, ZnR/GPR39 was shown to regulate the activity of ion transport mechanisms that are essential for the physiological function of epithelial and neuronal cells. Thus, ZnR/GPR39 provides a unique target for therapeutically modifying the actions of zinc in a specific and selective manner.
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10.
Importance of bicarbonate transport in pH control during amelogenesis - need for functional studies.
Varga, G, DenBesten, P, Rácz, R, Zsembery, Á
Oral diseases. 2018;(6):879-890
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Abstract
Dental enamel, the hardest mammalian tissue, is produced by ameloblasts. Ameloblasts show many similarities to other transporting epithelia although their secretory product, the enamel matrix, is quite different. Ameloblasts direct the formation of hydroxyapatite crystals, which liberate large quantities of protons that then need to be buffered to allow mineralization to proceed. Buffering requires a tight pH regulation and secretion of bicarbonate by ameloblasts. Many investigations have used immunohistochemical and knockout studies to determine the effects of these genes on enamel formation, but up till recently very little functional data were available for mineral ion transport. To address this, we developed a novel 2D in vitro model using HAT-7 ameloblast cells. HAT-7 cells can be polarized and develop functional tight junctions. Furthermore, they are able to accumulate bicarbonate ions from the basolateral to the apical fluid spaces. We propose that in the future, the HAT-7 2D system along with similar cellular models will be useful to functionally model ion transport processes during amelogenesis. Additionally, we also suggest that similar approaches will allow a better understanding of the regulation of the cycling process in maturation-stage ameloblasts, and the pH sensory mechanisms, which are required to develop sound, healthy enamel.