• Laboraroty Animal Research
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• v.34 no.4
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• pp.140-146
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• 2018

Though bile acids have been well known as digestive juice, recent studies have demonstrated that bile acids bind to their endogenous receptors, including Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1; TGR5) and serve as hormone to control various biological processes, including cholesterol/bile acid metabolism, glucose/lipid metabolism, immune responses, and energy metabolism. Deficiency of those bile acid receptors has been reported to induce diverse metabolic syndromes such as obesity, hyperlipidemia, hyperglycemia, and insulin resistance. As consistent, numerous studies have reported alteration of bile acid signaling pathways in type II diabetes patients. Interestingly, bile acids have shown to activate TGR5 in intestinal L cells and enhance secretion of glucagon-like peptide 1 (GLP-1) to potentiate insulin secretion in response to glucose. Moreover, FXR has been shown to crosstalk with TGR5 to control GLP-1 secretion. Altogether, bile acid receptors, FXR and TGR5 are potent therapeutic targets for the treatment of metabolic diseases, including type II diabetes.

• Biomolecules & Therapeutics
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• v.29 no.1
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• pp.22-30
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• 2021

Till the 21st century, fatty acids were considered as merely building blocks for triglycerides, phospholipids, or cholesteryl esters. However, the discovery of G protein-coupled receptors (GPCRs) for free fatty acids at the beginning of the 21st century challenged that idea and paved way for a new field of research, merged into the field of receptor pharmacology for intercellular lipid mediators. Among the GPCRs for free fatty acids, free fatty acid receptor 4 (FFA4, also known as GPR120) recognizes long-chain polyunsaturated fatty acids such as DHA and EPA. It is significant in drug discovery because it regulates obesity-induced metaflammation and GLP-1 secretion. Our study reviews information on newly developed FFA4 agonists and their application in pathophysiologic studies and drug discovery. It also offers a potency comparison of the FFA4 agonists in an AP-TGF-α shedding assay.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.5
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• pp.449-456
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• 2023

N-methyl-D-aspartate (NMDA) receptors are ionic glutamine receptors involved in brain development and functions such as learning and memory formation. NMDA receptor inhibition is associated with autophagy activation. In this study, we investigated whether the NMDA receptor antagonists, memantine and ifenprodil, induce autophagy in human retinal pigment epithelial cells (ARPE-19) to remove N-retinylidene-N-retinylethanolamine (A2E), an intracellular lipofuscin component. Fluorometric analysis using labeled A2E (A2E-BDP) and confocal microscopic examination revealed that low concentrations of NMDA receptor antagonists, which did not induce cytotoxicity, significantly reduced A2E accumulation in ARPE-19 cells. In addition, memantine and ifenprodil activated autophagy in ARPE-19 cells as measured by microtubule-associated protein 1A/1B-light chain3-II formation and phosphorylated p62 protein levels. Further, to understand the correlation between memantine- and ifenprodil-mediated A2E degradation and autophagy, autophagy-related 5 (ATG5) was depleted using RNA interference. Memantine and ifenprodil failed to degrade A2E in ARPE-19 cells lacking ATG5. Taken together, our study indicates that the NMDA receptor antagonists, memantine and ifenprodil, can remove A2E accumulated in cells via autophagy activation in ARPE-19 cells.

• Journal of Life Science
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• v.25 no.10
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• pp.1103-1109
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• 2015

Cholinergic innervation of the hippocampus is known to be correlated with learning and memory. The cholinergic agonist carbachol (CCh) modulate synaptic plasticity and produced long-term synaptic depression (LTD) in the hippocampus. However, the exact mechanisms by which the cholinergic system modifies synaptic functions in the hippocampus have yet to be determined. This study introduces an acetylcholine receptor-mediated LTD that requires internalization of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors on the postsynaptic surface and their intracellular mechanism in the hippocampus. In the present study, we showed that the application of the cholinergic agonist CCh reduced the surface expression of GluA2 on synapses and that this reduction was prevented by the M1 muscarinic acetylcholine receptor antagonist pirenzepine in primary hippocampal neurons. The interaction between GluA2 and the glutamate receptor-interacting protein 1 (GRIP1) was disrupted in a hippocampal slice from a rat upon CCh simulation. Under the same conditions, the binding of GluA2 to adaptin-α, a protein involved in clathrin-mediated endocytosis, was enhanced. The current data suggest that the activation of LTD, mediated by the acetylcholine receptor, requires the internalization of the GluA2 subunits of AMPA receptors and that this may be controlled by the disruption of GRIP1 in the PDZ ligand domain of GluA2. Therefore, we can hypothesize that one mechanism underlying the LTD mediated by the M1 mAChR is the internalization of the GluA2 AMPAR subunits from the plasma membrane in the hippocampal cholinergic system.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.5
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• pp.397-405
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• 2001

The ryanodine receptor, a $Ca^{2+}$ release channel of the sarcoplasmic reticulum (SR), is responsible for the rapid release of $Ca^{2+}$ that activates cardiac muscle contraction. In the excitation-contraction coupling cascade, activation of SR $Ca^{2+}$ release channel is initiated by the activity of sarcolemmal $Ca^{2+}$ channels, the dihydropyridine receptors. Previous study showed that the relaxation defect of diabetic heart was due to the changes of the expressional levels of SR $Ca^{2+}$ATPase and phospholamban. In the diabetic heart contractile abnormalities were also observed, and one of the mechanisms for these changes could include alterations in the expression and/or activity levels of various $Ca^{2+}$ regulatory proteins involving cardiac contraction. In the present study, underlying mechanisms for the functional derangement of the diabetic cardiomyopathy were investigated with respect to ryanodine receptor, and dihydropyridine receptor at the transcriptional and translational levels. Quantitative changes of ryanodine receptors and the dihydropyridine receptors, and the functional consequences of those changes in diabetic heart were investigated. The levels of protein and mRNA of the ryanodine receptor in diabetic rats were comparable to these of the control. However, the binding capacity of ryanodine was significantly decreased in diabetic rat hearts. Furthermore, the reduction in the binding capacity of ryanodine receptor was completely restored by insulin. This result suggests that there were no transcriptional and translational changes but functional changes, such as conformational changes of the $Ca^{2+}$ release channel, which might be regulated by insulin. The protein level of the dihydropyridine receptor and the binding capacity of nitrendipine in the sarcolemmal membranes of diabetic rats were not different as compared to these of the control. In conclusion, in diabetic hearts, $Ca^{2+}$ release processes are impaired, which are likely to lead to functional derangement of contraction of heart. This dysregulation of intracellular $Ca^{2+}$ concentration could explain for clinical findings of diabetic cardiomyopathy and provide the scientific basis for more effective treatments of diabetic patients. In view of these results, insulin may be involved in the control of intracellular $Ca^{2+}$ in the cardiomyocyte via unknown mechanism, which needs further study.

• The Korean Journal of Pharmacology
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• v.20 no.2
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• pp.23-34
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• 1984

To investigate diurnal variations of opiate receptor binding and its modification by experimental condition or treatment of various centrally-acting drugs, the amount of maximum $^3H-morphine$ binding in rat midbrain homogenates was measured at 4 hour intervals for 24 hours. Animals were conditioned under the controlled L : D, 12 : 12 cycle or D: D, 12 : 12 cycle, for 3 weeks and treated with 0.5 ml of physiological saline or drugs for 2 weeks. A highly significant diurnal rhythm with peak at 22 hour of early dark phase with an amplitude$(0.68{\pm}0.06\;pmole/mg\;protein)$ of +51.1% and nadir $(0.33{\pm}0.03\;mole/mg\;prtein)$ at 18 hour of late light phase with an amplitude of -26.6% was found in control group. 24 tour mean of $^3H-morphine$ binding was $0.45{\pm}0.03\;pmole/mg$ protein respectively. Constant dark adaptation or treatment of reserpine, pargyline, imipramine, amphetamine and chlorpromazine modified the diurnal rhythm in the time of peak and nadir binding shape, phase, amplitude of the diurnal curve and 24 hour mean of $^3H-morphine$ binding. However, Kd values were not changed in all experimental groups : Statistical analysis at times of least and great binding indicates that the differences in $^3H-morphine$ binding were due to changes not in the affinity, but in the number of binding sites. The results are interpreted with regard to the diurnal rhythm of opiate receptor finding. The modes of action of psychoactive drugs are closely related to postulated changes of receptor sensitivity in neuropharmacological aspects.

• Interdisciplinary Bio Central
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• v.5 no.3
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• pp.6.1-6.7
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• 2013

Many insects such as mosquitoes cause life-threatening diseases such as malaria, yellow fever and West Nile virus. Malaria alone infects 500 million people annually and causes 1-3 million death per year. Volatile insect repellents, which are detected through the sense of smell, have long been used to protect humans against insect pests. Antifeed-ants are non-volatile aversive compounds that are detected through the sense of taste and prevent insects from feeding on plants. The molecular targets and signaling path-ways required for sensing insect repellents and antifeedants are poorly understood. Transient Receptor Potential (TRP) Ca2+-permeable cation channels exist in organisms ranging from C. elegans to D. melanogaster and Homo sapiens. Drosophila has 13 family members, which mainly function in sensory physiology such as vision, thermotaxis and chemotaxis. G protein-coupled receptors (GPCRs) initiate olfactory signaling cascades in mammals and in nematodes C.elegans. However, the mechanisms of G protein signaling cascades in insect chemosensation are controversial. In this review, I will discuss the putative roles of G protein-coupled receptors (GPCRs) and Transient Receptor Potential (TRP) channels as targets for insect repellents.

• Journal of Life Science
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• v.13 no.5
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• pp.746-750
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• 2003

Lactose operon contains two CRP binding sites at promoter(CRP1 site) and operator(CRP2 site) regions at lac operon. CRP protein can bind to both sites with the different binding affinity. CRP1 site, major CRP binding site, acts the transcription activation with the fully unknown mechanism by binding of CRP. In this study, the binding affinities of CRP1 site and CRP2 site were measured with the fluorescein-labeled oligomers, which contain CRP1 site and the three different spacing sequences between GTGA and TCAC at CRP2 site. Results showed that CRP:cAMP complex bound to CRP1 site 3 times more strongly than CRP2 site and the base spacing between GTGA and TCAC was not the only factor to affect the binding affinity of CRP to CRP2 site.

• Bulletin of the Korean Chemical Society
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• v.18 no.1
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• pp.18-23
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• 1997

Data from structure/activity studies in vir gene induction system have led to evaluate the working hypothesis of interaction between phenolic inducers and phenol binding proteins. The primary specificity in the association of a phenolic inducer with its receptor in our system is hypothesized to be the hydrogen bonding interactions through the ortho methoxy substituents as well as the proton transfer between the inducer and the binding protein. In this paper the proposed working model for phenol-mediating signal transduction was evaluated in several ways. The importance of the general acid-base catalysis was first addressed by the presence of an acidic residue and a basic residue in the phenol binding protein. Series of compounds were tested for vir gene expression activity to confirm the generation of a strong nucleophile by an acidic residue and an involvement of a basic residue as a proton acceptor. An attempt was made to correlate the pKa values of the phenolic compounds with vir gene induction activities as inducers to further support the proposed proton transfer mechanism. Finally, it was also observed that the regioselectively attached methoxy group on phenol compounds is required as the proper hydrogen bond acceptor.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.89.2-89.2
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• 2003

Ral GDP dissociation stimulator (Ral GDS) has been found to be an effector protein of Ras, and Ral, a member of small GTP-binding protein (G protein) superfamily, has been suggested to act downstream of Ras. Ral GDP dissociation stimulator-like (RGL) shares 50% amino acid identity with Ral GDP dissociation stimulator, and assumed to possess similar functional role. Using yeast two-hybrid screening, we found that dopamine D3 receptor interacts with RGL. Since RGL is known to regulate the expression of c-fos promoter, effects of D3R on gene expression of c-fos promoter was studied. (omitted)