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( Chengchun Min ),( Mei Zheng ),( Xiaohan Zhang ),( Shuohan Guo ),( Kyoung-ja Kwon ),( Chan Young Shin ),( Hyeong-suk Kim ),( Seung Hoon Cheon ),( Kyeong-man Kim ) 전남대학교 약품개발연구소 2015 약품개발연구지 Vol.24 No.-
Numerous G protein-coupled receptots (GPCRs) are glycosylated at extacellular regions. The regulatory roles of glycosylation on receptor function vary across receptor types. In this study. we used the dopamine D₂ and D₃ receptors as an experimental model to understand the underlying principles governing the functional roles of glycosylation. We used the pharmacological inhibitor. tunicamycin, to inhibit glycosylation. generated chimeric D₂ and D₃ receptors by swapping their respective N-termini. and produced the glycosylation site mutant D₂ and D₃ receptors to study the roles of glycosylation on receptor functions, induding cell surface expression, signaling, and internalization through specific microdomains. Our results demonstrate that glycosylation on the N-terminus of the D₃ receptor is involved in the development of desensitization and proper cell surface expression. In addition, glycosylation on the N-terminus mediates the internalization of D₂ and D₃, receptors within the caveolae and clathrin-coated pit microdomains of the plasma membrane, respectively, by regulating receptor interactions with caveolin-1 and c1athrin. In conclusion, this study shows for the first time that glycosylation on the N-terminus of GPCRs is involved in endocytic pathway selection through specific microdomains. These data suggest that changes in the cellular environment that influence posttranslational modification could be an important determinant of intracellular GPCR trafficking.
Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors
( Chengchun Min ),( Xiaohan Zhang ),( Mei Zheng ),( Ningning Sun ),( Srijan Acharya ),( Xiaowei Zhang ),( Kyeong-man Kim ) 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.3
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 β-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 β-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, β-arrestin2, and Gβγ. Gβγ displayed a stable interaction with receptors and b-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 Gβγ and β-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and Gβγ complex is required for the formation of a complex with β-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, β-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and Gβγ.
Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors
Min, Chengchun,Zhang, Xiaohan,Zheng, Mei,Sun, Ningning,Acharya, Srijan,Zhang, Xiaowei,Kim, Kyeong-Man The Korean Society of Applied Pharmacology 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.3
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 $G{\beta}{\gamma}$.
Functional Regulation of Dopamine D₃ Receptor through Interaction with PICK1
( Mei Zheng ),( Xiaohan Zhang ),( Chengchun Min ),( Bo-gil Choi ),( In-joon Oh ),( Kyeong-man Kim ) 한국응용약물학회 2016 Biomolecules & Therapeutics(구 응용약물학회지) Vol.24 No.5
PICK1, a PDZ domain-containing protein, is known to increase the reuptake activities of dopamine transporters by increasing their expressions on the cell surface. Here, we report a direct and functional interaction between PICK1 and dopamine D₃ receptors (D₃R), which act as autoreceptors to negatively regulate dopaminergic neurons. PICK1 colocalized with both dopamine D₂ receptor (D₂R) and D₃R in clusters but exerted different functional influences on them. The cell surface expression, agonist affinity, endocytosis, and signaling of D₂R were unaffected by the coexpression of PICK1. On the other hand, the surface expression and tolerance of D₃R were inhibited by the coexpression of PICK1. These findings show that PICK1 exerts multiple effects on D₃R functions.
Functional Regulation of Dopamine D<sub>3</sub> Receptor through Interaction with PICK1
Zheng, Mei,Zhang, Xiaohan,Min, Chengchun,Choi, Bo-Gil,Oh, In-Joon,Kim, Kyeong-Man The Korean Society of Applied Pharmacology 2016 Biomolecules & Therapeutics(구 응용약물학회지) Vol.24 No.5
PICK1, a PDZ domain-containing protein, is known to increase the reuptake activities of dopamine transporters by increasing their expressions on the cell surface. Here, we report a direct and functional interaction between PICK1 and dopamine $D_3$ receptors ($D_3R$), which act as autoreceptors to negatively regulate dopaminergic neurons. PICK1 colocalized with both dopamine $D_2$ receptor ($D_2R$) and $D_3R$ in clusters but exerted different functional influences on them. The cell surface expression, agonist affinity, endocytosis, and signaling of $D_2R$ were unaffected by the coexpression of PICK1. On the other hand, the surface expression and tolerance of $D_3R$ were inhibited by the coexpression of PICK1. These findings show that PICK1 exerts multiple effects on $D_3R$ functions.
Ju-Heon Kim,Eun-Young Cho,Chengchun Min,Jae H. Park,김경만 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.4
Dopamine D2R and D3R (D2R, D3R) show very high sequence homology and employ virtually identical signaling pathways even though D2R is 2 ~ 5 times more active. Among the structural motifs identified, a triplet sequence, Asp-Arg-Tyr (DRY motif), plays critical roles in the determination of receptor conformations for signaling and intracellular trafficking of G protein-coupled receptors by forming intramolecular interactions. Thus, it is possible that different signaling efficiencies of D2R and D3R might be caused by the receptor activation levels stabilized by their own DRY motifs. In this study, the Arg and Asp residues of D2R and D3R were mutated, and resulting changes in their signaling and intracellular trafficking properties were comparatively studied. Mutation of the Arg residues of D2R and D3R abolished their signaling but differently affected their intracellular localizations. The wildtype and R132H-D2R were expressed mainly on the plasma membrane. On the other hand, compared with the wildtype D3R, a substantial amount of R128H-D3R was localized intracellularly. The expression of receptor proteins on the plasma membrane and their signaling efficiencies were more drastically affected by the mutation of the Asp residue of D3R than D2R. Therefore, it was concluded that the different levels of conformational strain exerted by the DRY motif might partly determine the quantitative differences in the signaling efficiencies between D2R and D3R.