• Biomolecules & Therapeutics
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• v.32 no.1
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• pp.56-64
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• 2024

Biased signaling or functional selectivity refers to the ability of an agonist or receptor to selectively activate a subset of transducers such as G protein and arrestin in the case of G protein-coupled receptors (GPCRs). Although signaling through arrestin has been reported from various GPCRs, only a few studies have examined side-by-side how it differs from signaling via G protein. In this study, two signaling pathways were compared using dopamine D₂ receptor (D₂R) mutants engineered via the evolutionary tracer method to selectively transduce signals through G protein or arrestin (D₂G and D₂Arr, respectively). D₂G mediated the inhibition of cAMP production and ERK activation in the cytoplasm. D₂Arr, in contrast, mediated receptor endocytosis accompanied by arrestin ubiquitination and ERK activation in the nucleus as well as in the cytoplasm. D₂Arr-mediated ERK activation occurred in a manner dependent on arrestin3 but not arrestin2, accompanied by the nuclear translocation of arrestin3 via importin1. D₂R-mediated ERK activation, which occurred in both the cytosol and nucleus, was limited to the cytosol when cellular arrestin3 was depleted. This finding supports the results obtained with D₂Arr and D₂G. Taken together, these observations indicate that biased signal transduction pathways activate distinct downstream mechanisms and that the subcellular regions in which they occur could be different when the same effectors are involved. These findings broaden our understanding on the relation between biased receptors and the corresponding downstream signaling, which is critical for elucidating the functional roles of biased pathways.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.6
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• pp.661-670
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• 1998

Dopamine has been generally known to exert antinociceptive action in behavioral pain test, such as tail flick and hot plate test, but there appears to be a great variance in the reports on the antinociceptive effect of dopamine depending on the dosage and route of drug administration and type of animal preparation. In the present study, the effects of dopamine on the responses of wide dynamic range (WDR) cells to mechanical, thermal and graded electrical stimuli were investigated, and the dopamine-induced changes in WDR cell responses were compared between animals with an intact spinal cord and the spinal animals. Spinal application of dopamine (1.3 & 2.6 mM) produced a dose-dependent inhibiton of WDR cell responses to afferent inputs, the pinch-induced or the C-fiber evoked responses being more strongly depressed than the brush-induced or the A-fiber evoked responses. The dopamine-induced inhibition was more pronounced in the spinal cat than in the cat with intact spinal cord. The responses of WDR cell to thermal stimulation were also strongly inhibited. Dopamine $D_2$ receptor antagonist, sulpiride, but not $D_1$ receptor antagonist, significantly blocked the inhibitory action of dopamine on the C-fiber and thermal responses of dorsal horn cells. These findings suggest that dopamine strongly suppresses the responses of WDR cells to afferent signals mainly through spinal dopamine $D_2$ receptors and that spinal dopaminergic processes are under the tonic inhibitory action of the descending supraspinal pathways.

• Archives of Pharmacal Research
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• v.18 no.4
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• pp.249-255
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• 1995

The changes in the levels of the extracellular dopamine metabolites and the responses to various dopamine agents were studied by using microdialysis inhyperglycemic rat striatum. The hyperglycemia were induced by the administriation of streptozotocin (40 mg/kg, i.p. for 3 days.). The basal levels of striatal dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were significantly decreased in hyperglycemic rat striatum. After the administration ofl D-1 and D-2 receptor antagonists, SCH-23390 and (-)sulpiride, to rats 14 days after the last administration of STZ, the increased rates in DOPAC levels were higher in hyper- than in normoglycemic rats. However, after the administration of dopamine autoeceptor agonist, 3(-)PPP, the levels of the extracellular HVA were increased in normoglycemic rats, but those were not altered in hyperglycemic rats. The results indicate that the striatal dopamine activities were decreased in the hyperglycemic rats and suggest that release of dopamine may be decreased in hyperglycemic rats. Furthermore it suggest that the increase in the levels of the extracellular dopamine metabolites by dopamine antagonists might be dur to the incrrased sensitivities of the dopamine receptors in hyperglycemic state.

• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.108-115
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• 2023

Numerous psychotropic and addictive substances possess structural features similar to those of β-phenethylamine (β-PEA). In this study, we selected 29 β-PEA derivatives and determined their structure-activity relationship (SAR) to their ability to inhibit dopamine (DA) reuptake; conducted docking simulation for two selected compounds; and identified their potential functionals. The compounds were subdivided into arylethylamines, 2-(alkyl amino)-1-arylalkan-1-one derivatives and alkyl 2-phenyl-2-(piperidin-2-yl)acetate derivatives. An aromatic group, alkyl group, and alkylamine derivative were attached to the arylethylamine and 2-(alkyl amino)-1-arylalkan-1-one derivatives. The inhibitory effect of the compounds on dopamine reuptake increased in the order of the compounds substituted with phenyl, thiophenyl, and substituted phenyl groups in the aromatic position; compounds with longer alkyl groups and smaller ring-sized compounds at the alkylamine position showed stronger inhibitory activities. Docking simulation conducted for two compounds, 9 and 28, showed that the (S)-form of compound 9 was more stable than the (R)-form, with a good fit into the binding site covered by helices 1, 3, and 6 of human dopamine transporter (hDAT). In contrast, the (R, S)-configuration of compound 28 was more stable than that of other isomers and was firmly placed in the binding pocket of DAT bound to DA. DA-induced endocytosis of dopamine D₂ receptors was inhibited when they were co-expressed with DAT, which lowered extracellular DA levels, and uninhibited when they were pretreated with compound 9 or 28. In summary, this study revealed critical structural features responsible for the inhibition of DA reuptake and the functional role of DA reuptake inhibitors in regulating D₂ receptor function.

• YAKHAK HOEJI
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• v.52 no.6
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• pp.488-493
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• 2008

2-Aminothiazole ring as a bioisoster of catechol in dopamine has provided with good oral availability and lipophilic property. 2-Aminoindan, is a rigid form of dopamine, was evaluated as a dopamine D3 agonist with low neurotoxicity. Dopamine D3 agonist was evaluated as selective for the treatment of Parkinson's disease. In order to develop a novel dopamine D3 agonist, we tried to synthesize the aminothiazoloindenoxazine derivative that is a hybrid structure of aminoindenoxazine and thiazole ring. cis-2-Amino-1-indanol (2) was synthesized from 1,2-indandione-2-oxime by catalytic hydrogenation and it was treated with chloroacetyl chloride and NaH in benzene solution to give (${\pm}$)-cis-4,4a,5,9b-tetrahydroindeno[1,2-b][1,4]oxazin-3(2H)-one (6). Nitration of 6 by the mixed acid gave 8-nitro compound (7) and the carbonyl group of 7 was reduced with $LiAlH_4$ to afford compound (8). 8 was reduced to form (${\pm}$)-cis-8-amino-2,3,4,4a,5,9b-hexahydroindeno[1,2-b][1,4]oxazine (9) and finally it was cyclized with KSCN in glacial acetic acid to yield (${\pm}$)-cis-8-amino-2,3,4,4a,5,10b-hexahydrothiazolo[4,5-f]indeno[1,2-b][1,4]oxazine (10).

• Toxicological Research
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• v.20 no.1
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• pp.49-53
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• 2004

The genetic basis of hypertension is complex, and has been considered to be associated with the dopamine D2 receptor gene (DD2R). Because association studies using the candidate gene approach may provide important clues regarding the pathogenesis of hypertension and establish basis for further study, we performed the association study on the relationship between genetic polymorphisms in the DD2R gene and hypertension in Koreans. Eighty nine patients with hypertension and 86 age-matched subjects with normal blood pressure were enrolled. Genomic DNA was extracted from peripheral blood leukocytes. PCR-RFLP analysis was performed to detect the three polymorphic Taq I sites in the DD2R gene. There were no significant differences in genotype, allele and haplotype distributions of any polymorphisms in the DD2R gene between two groups, respectively (P>0.05), although significant linkage disequilibriums among these polymorphic sites were detected by pair-wise analysis (P<0.05). Therefore, our negative result suggest that the three Taq I RFLPs in the DD2R gene were not significantly associated with hypertension in Koreans.

• Proceedings of the Zoological Society Korea Conference
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• 1996.04a
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• pp.46.1-46
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• 1996

No Abstract, See Full Text

• Molecules and Cells
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• v.26 no.3
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• pp.243-249
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• 2008

Corticotropin releasing factor (CRF) mediates various responses to stress through CRF receptors 1 and 2. CRF receptor 2 has two forms, $2{\alpha}$ and $2{\beta}$ each of which appears to have distinct roles. Here we used dopaminergic neuron-derived MN9D cells to investigate the function of CRF receptor 2 in dopamine neurons. We found that n-butyrate, a histone deacetylase inhibitor, induced MN9D cell differentiation and increased gene expression of all CRF receptors. CRF receptor $2{\beta}$ was minimally expressed in MN9D cells; however, its expression dramatically increased during differentiation. CRF receptor $2{\beta}$ expression levels appeared to correlate with neurite outgrowth, suggesting CRF receptor $2{\beta}$ involvement in neuronal differentiation. To validate this statement, we made a CRF receptor $2{\beta}$-overexpressing $MN9D/CRFR2{\beta}$ stable cell line. This cell line showed robust neurite outgrowth and GAP43 overexpression, together with MEK and ERK activation, suggesting MN9D cell neuronal differentiation. From these results, we conclude that CRF receptor $2{\beta}$ plays an important role in MN9D cell differentiation by activating the MEK/ERK signaling pathway.

• Proceedings of the PSK Conference
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• 2001.04a
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• pp.124.2-124.2
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• 2001

• Proceedings of the PSK Conference
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• 2000.04a
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• pp.116.2-116.2
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• 2000