• Biomolecules & Therapeutics
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• v.25 no.3
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• pp.239-248
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• 2017

Desensitization and acute tolerance are terms used to describe the attenuation of receptor responsiveness by prolonged or intermittent exposure to an agonist. Unlike desensitization of G protein-coupled receptors (GPCRs), which is commonly explained by steric hindrance caused by the ${\beta}$-arrestins that are translocated to the activated receptors, molecular mechanisms involved in the acute tolerance of GPCRs remain unclear. Our studies with several GPCRs and related mutants showed that the acute tolerance of GPCRs could occur independently of agonist-induced ${\beta}$-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, ${\beta}$-arrestin2, and $G{\beta}{\gamma}$. $G{\beta}{\gamma}$ displayed a stable interaction with receptors and ${\beta}$-arrestin2 in cells expressing GPCRs that were prone to undergo tolerance compared to the GPCRs that were resistant to acute tolerance. Strengthening the interaction between $G{\beta}{\gamma}$ and ${\beta}$-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and $G{\beta}{\gamma}$ complex is required for the formation of a complex with ${\beta}$-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, ${\beta}$-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and $G{\beta}{\gamma}$.

• The Korean Journal of Nuclear Medicine
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• v.18 no.2
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• pp.17-23
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• 1984

For nearly a century it has been known that chemical activity accompanies mental activity, but only recently has it been possible to begin to examine its exact nature. Positron-emitting radioactive tracers have made it possible to study the chemistry of the human mind in health and disease, using chiefly cyclotron-produced radionuclides, carbon-11, fluorine-18 and oxygen-15. It is now well established that measurable increases in regional cerebral blood flow, glucose and oxygen metabolism accompany the mental functions of perception, cognition, emotion and motion. On May 25, 1983 the first imaging of a neuroreceptor in the human brain was accomplished with carbon-11 methyl spiperone, a ligand that binds preferentially to dopamine-2 receptors, 80% of which are located in the caudate nucleus and putamen. Quantitative imaging of serotonin-2, opiate, benzodiazapine and muscarinic cholinergic receptors has subsequently been accomplished. In studies of normal men and women, it has been found that dopamine and serotonin receptor activity decreases dramatically with age, such a decrease being more pronounced in men than in women and greater in the case of dopamine receptors than serotonin-2 receptors. Preliminary studies in patients with neuropsychiatric disorders suggests that dopamine-2 receptor activity is diminished in the caudate nucleus of patients with Huntington's disease. Positron tomography permits quantitative assay of picomolar quantities of neuro-receptors within the living human brain. Studies of patients with Parkinson's disease, Alzheimer's disease, depression, anxiety, schizophrenia, acute and chronic pain states and drug addiction are now in progress. The growth of any scientific field is based on a paradigm or set of ideas that the community of scientists accepts. The unifying principle of nuclear medicine is the tracer principle applied to the study of human disease. Nineteen hundred and sixty-three was a landmark year in which technetium-99m and the Anger camera combined to move the field from its latent stage into a second stage characterized by exponential growth within the framework of the paradigm. The third stage, characterized by gradually declining growth, began in 1973. Faced with competing advances, such as computed tomography and ultrasonography, proponents and participants in the field of nuclear medicine began to search for greener pastures or to pursue narrow sub-specialties. Research became characterized by refinements of existing techniques. In 1983 nuclear medicine experienced what could be a profound change. A new paradigm was born when it was demonstrated that, despite their extremely low chemical concentrations, in the picomolar range, it was possible to image and quantify the distribution of receptors in the human body. Thus, nuclear medicine was able to move beyond physiology into biochemistry and pharmacology. Fundamental to the science of pharmacology is the concept that many drugs and endogenous substances, such as neurotransmitters, react with specific macromolecules that mediate their pharmacologic actions. Such receptors are usually identified in the study of excised tissues, cells or cell membranes, or in autoradiographic studies in animals. The first imaging and quantification of a neuroreceptor in a living human being was performed on May 25, 1983 and reported in the September 23, 1983 issue of SCIENCE. The study involved the development and use of carbon-11 N-methyl spiperone (NMSP), a drug with a high affinity for dopamine receptors. Since then, studies of dopamine and serotonin receptors have been carried out in over 100 normal persons or patients with various neuropsychiatric disorders. Exactly one year later, the first imaging of opitate receptors in a living human being was performed [1].

• BMB Reports
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• v.46 no.2
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• pp.107-112
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• 2013

Although BMP6 is highly capable of inducing osteogenic differentiation of mesenchymal progenitor cells (MPCs), the molecular mechanism involved remains to be fully elucidated. Using dominant negative (dn) mutant form of type I and type II $TGF{\beta}$ receptors, we demonstrated that three dn-type I receptors (dnALK2, dnALK3, dnALK6), and three dn-type II receptors (dnBMPRII, dnActRII, dnActRIIB), effectively diminished BMP6-induced osteogenic differentiation of MPCs. These findings suggested that ALK2, ALK3, ALK6, BMPRII, ActRII and ActRIIB are essential for BMP6-induced osteogenic differentiation of MPCs. However, MPCs in this study do not express ActRIIB. Moreover, RNA interference of ALK2, ALK3, ALK6, BMPRII and ActRII inhibited BMP6-induced osteogenic differentiation in MPCs. Our results strongly suggested that BMP6-induced osteogenic differentiation of MPCs is mediated by its functional $TGF{\beta}$ receptors including ALK2, ALK3, ALK6, BMPRII, and ActRII.

• ALGAE
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• v.36 no.4
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• pp.315-326
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• 2021

Ion channels are membrane protein complexes mediating passive ion flux across the cell membranes. Every organism has a certain set of ion channels that define its physiology. Dinoflagellates are ecologically important microorganisms characterized by effective physiological adaptability, which backs up their massive proliferations that often result in harmful blooms (red tides). In this study, we used a bioinformatics approach to identify homologs of known ion channels that belong to 36 ion channel families. We demonstrated that the versatility of the dinoflagellate physiology is underpinned by a high diversity of ion channels including homologs of animal and plant proteins, as well as channels unique to protists. The analysis of 27 transcriptomes allowed reconstructing a consensus ion channel repertoire (channelome) of dinoflagellates including the members of 31 ion channel families: inwardly-rectifying potassium channels, two-pore domain potassium channels, voltage-gated potassium channels (K_v), tandem K_v, cyclic nucleotide-binding domain-containing channels (CNBD), tandem CNBD, eukaryotic ionotropic glutamate receptors, large-conductance calcium-activated potassium channels, intermediate/small-conductance calcium-activated potassium channels, eukaryotic single-domain voltage-gated cation channels, transient receptor potential channels, two-pore domain calcium channels, four-domain voltage-gated cation channels, cation and anion Cys-loop receptors, small-conductivity mechanosensitive channels, large-conductivity mechanosensitive channels, voltage-gated proton channels, inositole-1,4,5-trisphosphate receptors, slow anion channels, aluminum-activated malate transporters and quick anion channels, mitochondrial calcium uniporters, voltage-dependent anion channels, vesicular chloride channels, ionotropic purinergic receptors, animal volage-insensitive cation channels, channelrhodopsins, bestrophins, voltage-gated chloride channels H⁺/Cl^- exchangers, plant calcium-permeable mechanosensitive channels, and trimeric intracellular cation channels. Overall, dinoflagellates represent cells able to respond to physical and chemical stimuli utilizing a wide range of G-protein coupled receptors- and Ca²⁺-dependent signaling pathways. The applied approach not only shed light on the ion channel set in dinoflagellates, but also provided the information on possible molecular mechanisms underlying vital cellular processes dependent on the ion transport.

• Toxicological Research
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• v.21 no.4
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• pp.333-338
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• 2005

Many of thyroid hormones disrupting chemicals induce effects via interaction with thyroid hormone and retinoic acid receptors and responsive elements intrinsic in target cells. We studied thyroid hormones disrupting effects of food additives and contaminants including BHA, BHT, ethoxyquin, propionic acid, sorbic acid, benzoic acid, CPM, aflatoxin B1, cadmium chloride, genistein, TCDD, PCBs and TDBE in recombinant HeLa cells containing plasmid construct for thyroxin responsive elements. The limit of response of the recombinant cells to T3 and T4 was $1\times10^{-12}\;M$. BHA. genistein, cadmium and TBDE were interacted with thyroid receptors with dose-responsive pattern. In addition, BHA, BHT, ethoxyquin, propionic acid, benzoic acid, sorbic acid, and TBDE showed synergism while cadmium chloride antagonism for T3-induced activity. This study elucidates that recombinant HeLa cell is sensitive and high-throughput system for the detection of chemicals that induce thyroid hormonal disruption via thyroid hormone receptors and responsive elements. Also this study raised suspect of BHA. BHT, ethoxyquin, propionic acid, benzoic acid, sorbic acid, TBDE, genisteine and cadmium chloride as thyroid hormonal system disruptors.

• Tuberculosis and Respiratory Diseases
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• v.49 no.4
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• pp.486-494
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• 2000

Background : The dominant innervation of airway smooth muscle is parasympathetic fibers which are carried in the vagus nerve. Activation of these cholinergic nerves releases acetylcholine which binds to $M_3$ muscarinic receptors on the smooth muscle causing bronchocontraction. Acetylcholine also feeds back onto neuronal $M_2$ muscarinic receptors located on the postganglionic cholinergic nerves. Stimulation of these receptors further inhibits acetylcholine release, so these $M_2$, muscarinic receptors act as autoreceptors. Loss of function of these $M_2$ receptors, as it occurs in animal models of hyperresponsiveness, leads to an increase in vagally mediated hyperresponsiveness. However, there are limited data pertaining to whether there are dysfunctions of these receptors in patients with asthma. The aim of this study is to determine whether there are dysfunction of $M_2$ muscarinic receptors in asthmatic patients and difference of function of these receptors according to severity of asthma. Method : We studied twenty-seven patients with asthma who were registered at Pulmonology Division of Korea University Hospital. They all met asthma criteria of ATS. Of these patients, eleven patients were categorized as having mild asthma, eight patients moderate asthma and eight patients severe asthma according to severity by NAEPP Expert Panel Report 2(1997). All subjects were free of recent upper respiratory tract infection within 2 weeks and showed positive methacholine challenge test ($PC_{20}$<16mg/ml). Methacholine provocation tests were performed twice on separate days allowing for an interval of one week. In the second test, pretreatment with the $M_2$ muscarinic receptor agonist pilocarpine($180{\mu}g$) through inhalation was performed be fore the routine procedures. Results : Eleven subjects with mild asthma and eight subjects with moderate asthma showed significant increase of $PC_{20}$ from 5.30$\pm$5.23mg/ml(mean$\pm$SD) to 20.82$\pm$22.56mg/ml(p=0.004) and from 2.79$\pm$1.51mg/ml to 4.67$\pm$3.53mg/ml(p=0.012) after pilocarpine inhalation, respectively. However, in the eight subjects with severe asthma significant increase of $PC_{20}$ from l.76$\pm$1.50mg/ml to 3.18$\pm$4.03mg/ml(p=0.161) after pilocarpine inhalation was not found. Conclusion : In subjects with mild and moderate asthma, function of $M_2$ muscarinic receptors was normal, but there was a dysfunction of these receptors in subjects with severe asthma. ηlese results suggest that function of $M_2$ muscarinic receptors is different according to severity of asthma.

• Food Science and Industry
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• v.50 no.4
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• pp.12-23
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• 2017

Gustation, initiated by the detection of taste molecules by specific receptors expressed in taste cells, plays an essential role in food selection and consequently in overall nutrition for humans. In the past decade, a remarkable amount of knowledge of taste perception in the neurology, molecular biology, and genetics has emerged, particularly in basic tastes- sweet, bitter, sour, salt and umami. Among them, sweet, bitter and umami are recognized via the specific G-protein coupled receptors. Salt and sour are primarily mediated by apically located ion channel-type receptors. Because excessive salt or sugar consumption leads to high rates of diet-associated diseases and it comes from eating prepared or processed foods, an understanding of the underlying mechanisms in salt and sweet perception is crucial in food industry. This review will focus on recent progress of the perception of salt and sweet taste to provide basic knowledge for reducing salt and sugar consumption.

• BMB Reports
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• v.56 no.4
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• pp.209-215
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• 2023

Maintaining internal homeostasis and regulating innate behaviors are essential for animal survival. In various animal species, a highly conserved neuroendocrine system integrates sensory inputs and regulates physiological responses to environmental and internal changes. Diuretic hormones 44 and 31, which are homologs of mammalian corticotropin-releasing factor (CRF) and calcitonin gene-related peptide (CGRP), respectively, control body fluid secretion in Drosophila. These neuropeptides and their receptors have multiple physiological roles, including the regulation of body-fluid secretion, sleep:wake cycle, internal nutrient-sensing, and CO₂-dependent response. This review discusses the physiological and behavioral roles of DH44 and DH31 signaling pathways, consisting of neuroendocrine cells that secrete DH44 or DH31 peptides and their receptor-expressing organs. Further research is needed to understand the regulatory mechanisms of the behavioral processes mediated by these neuroendocrine systems.

• Molecules and Cells
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• v.21 no.2
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• pp.174-185
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• 2006

Toll-like receptors (TLRs) were evolved to detect invading pathogens and to induce innate immune responses in order to mount host defense mechanisms. It becomes apparent that the activation of certain TLRs is also modulated by endogenous molecules including lipid components, fatty acids. Results from epidemiological and animal studies demonstrated that saturated and polyunsaturated dietary fatty acids can differentially modify the risk of development of many chronic diseases. Inflammation is now recognized as an important underlying etiologic condition for the pathogenesis of many chronic diseases. Therefore, if the activation of TLRs and consequent inflammatory and immune responses are differentially modulated by types of lipids in vivo, this would suggest that the risk of the development of chronic inflammatory diseases and the host defense against microbial infection may be modified by the types of dietary fat consumed.

• Anatomy and Cell Biology
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• v.56 no.2
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• pp.166-178
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• 2023

Undeniably, endothelial cells (EC) contribute to the maintenance of the homeostasis of the organism through modulating cellular physiology, including signaling pathways, through the release of highly active molecules as well as the response to a myriad of extrinsic and intrinsic signaling factors. Review the data from the current literature on the EC role in norm and disease. Endothelium maintains a precise balance between the released molecules, where EC dysfunction arises when the endothelium actions shift toward vasoconstriction, the proinflammatory, prothrombic properties after the alteration of nitric oxide (NO) production and oxidative stress. The functions of the EC are regulated by the negative/positive feedback from the organism, through EC surface receptors, and the crosstalk between NO, adrenergic receptors, and oxidative stress. More than a hundred substances can interact with EC. The EC dysfunction is a hallmark in the emergence and progression of vascular-related pathologies. The paper concisely reviews recent advances in EC (patho) physiology. Grasping EC physiology is crucial to gauge their potential clinical utility and optimize the current therapies as well as to establish novel nanotherapeutic molecular targets include; endothelial receptors, cell adhesion molecules, integrins, signaling pathways, enzymes; peptidases.