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      • KCI등재

        Sphingosine-1-Phosphate Receptors: Zooming in on Ligand-Induced Intracellular Trafficking and Its Functional Implications

        Verzijl, Dennis,Peters, Stephan L.M.,Alewijnse, Astrid E. Korean Society for Molecular and Cellular Biology 2010 Molecules and cells Vol.29 No.2

        Regulatory processes including receptor phosphorylation and intracellular trafficking, also referred to as receptor internalization, are important processes to terminate G protein-coupled receptor (GPCR) signaling. Compelling evidence now indicates that internalization of a receptor is not necessarily the endpoint of signaling, but can also be the beginning of the activation of intracellular signaling pathways. Sphingosine-1-phosphate (S1P) receptors, which are activated by the endogenous phospholipid S1P, belong to the family of GPCRs. Interestingly, there is evidence indicating differential intracellular trafficking of one of the S1P receptor subtypes, the S1P1 receptor, upon agonist activation by either S1P or the synthetic agonist FTY720-P. Moreover, the differential effect of FTY720-P on $S1P_1$ receptor regulation has been suggested to be the mechanism of action of this drug, which is now in Phase III clinical trials for the treatment of multiple sclerosis. It is thus of importance to get a good insight into the regulation of S1P receptors. This review therefore gives a detailed overview about the current state of knowledge on S1P receptor internalization and its functional implications, including some data on nuclear signaling of S1P receptors.

      • SCIESCOPUSKCI등재

        Analysis of a Sphingosine 1-phosphate Receptor hS1P<SUB>3</SUB> in Rat Hepatoma Cells

        Dong-Soon Im 대한생리학회-대한약리학회 2002 The Korean Journal of Physiology & Pharmacology Vol.6 No.3

        <P> To examine intracellular signaling of human S1P<SUB>3 </SUB>(hS1P<SUB>3</SUB>), a sphingosine 1-phosphate (S1P) receptor in plasma membrane, hS1P<SUB>3</SUB> DNA was transfected into RH7777 rat hepatoma cell line, and the inhibition of forskolin-induced cAMP accumulation and activation of MAP kinases by S1P were tested. In hS1P<SUB>3</SUB> transformants, S1P inhibited forskolin-induced activation of adenylyl cyclase activity by about 80% and activated MAP kinases in dose-dependent and pertussis-toxin (PTX) sensitive manners. In oocytes expressing hS1P<SUB>3</SUB> receptor, S1P evoked Cl<SUP>⁣</SUP> conductance. These data suggested that PTX-sensitive G proteins are involved in hS1P<SUB>3</SUB>-mediated signaling, especially the positive action of S1P in cell proliferation. The potential advantages of rat hepatoma cells for the research of sphingosine 1-phosphate receptor are discussed.

      • KCI등재

        Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

        박수진,임동순 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.1

        Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P1-5. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn’s disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.

      • KCI등재

        Sphingosine-1-Phosphate-Induced Migration and Differentiation of Human Mesenchymal Stem Cells to Smooth Muscle Cells

        Hae Young Song(송해영),Sang Hun Shin(신상훈),Min Young Kim(김민영),Jae Ho Kim(김재호) 한국생명과학회 2011 생명과학회지 Vol.21 No.2

        중간엽 줄기세포의 이동과 분화는 손상된 조직의 재생을 위해 필수적이다. Sphingosine-1-phosphate (S1P)는 세포성장, 생존, 분화, 이동성 등 여러 가지 생명현상에 중요한 역할을 하는 생리활성 지질이다. 본 연구에서는 인체 골수유래 중간엽 줄기세포의 이동과 세포분화에 대한 S1P의 영향을 조사하였다. S1P는 중간엽 줄기세포의 이동을 증가시켰으며 pertussis toxin의 전처리는 S1P에 의한 세포이동을 억제하였다. 본 결과는 S1P에 의한 세포이동과정에 Gi에 연결된 수용체가 관여함을 제시한다. S1P₁과 S1P₃ 수용체에 대한 길항제인 VPC23019의 전처리나 siRNA를 이용한 S1P₁ 수용체의 발현억제는 S1P에 의한 세포 내 칼슘 증가와 중간엽 줄기세포의 이동을 저해하였다. 또한, S1P의 처리는 중간엽 줄기세포에서 평활근세포의 표지유전자인 α-smooth muscle actin (α-SMA)의 발현을 증가시켰으며 VPC23019의 전처리는 S1P에 의한 α-SMA의 발현증가를 저해하였다. S1P는 중간엽 줄기세포에서 p38 mitogen-activated protein kinase (p38 MAPK)의 인산화를 촉진하였으며 p38 MAPK의 저해제인 SB202190의 전처리 또는 p38 MAPK의 dominant negative mutant의 과발현은 S1P에 의한 중간엽 줄기세포의 이동 α-SMA 발현증가를 억제하였다. 본 연구결과는 S1P가 S1P1-p38 MAPK 신호전달기전을 통해 중간엽 줄기세포의 이동과 평활근세포로의 분화를 촉진함으로써 중간엽 줄기세포를 이용한 조직재생에의 활용 가능성을 제시한다. Migration and differentiation of mesenchymal stem cells are crucial for tissue regeneration in response to injury. Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates a variety of biological processes, including proliferation, survival, differentiation and motility. In the present study, we determined the role of S1P in migration and differentiation of human bone marrow-derived mesenchymal stem cells (BMSCs). S1P stimulated migration of BMSCs in a dose- and time-dependent manner, and pre-incubation of the cells with pertussis toxin completely abrogated S1P-induced migration, suggesting involvement of Gi-coupled receptors in S1P-induced cell migration. S1P elicited elevation of intracellular concentration of Ca<SUP>2+</SUP> ([Ca<SUP>2+</SUP>]i) and pretreatment with VPC23019, an antagonist of S1P₁/S1P₃, blocked S1P-induced migration and increase of [Ca<SUP>2+</SUP>]i. Small interfering RNA-mediated knockdown of endogenous S1P1 attenuated S1P-induced migration of BMSCs. Furthermore, S1P treatment induced expression of α-smooth muscle actin (α-SMA), a smooth muscle marker, and pretreatment with VPC23019 abrogated S1P-induced α-SMA expression. S1P induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), and pretreatment of cells with SB202190, an inhibitor of p38 MAPK, or adenoviral overexpression of a dominant-negative mutant of the p38 MAPK blocked S1P-induced cell migration and α-SMA expression. Taken together, these results suggest that S1P stimulates migration and smooth muscle differentiation of BMSCs through an S1P1-p38 MAPK-dependent mechanism.

      • KCI등재

        Sphingosine-1-Phosphate Receptors: Zooming in on Ligand-Induced Intracellular Trafficking and Its Functional Implications

        Dennis Verzijl,Stephan L.M. Peters,Astrid E. Alewijnse 한국분자세포생물학회 2010 Molecules and cells Vol.29 No.2

        Regulatory processes including receptor phosphorylation and intracellular trafficking, also referred to as receptor internalization, are important processes to terminate G protein-coupled receptor (GPCR) signaling. Compelling evidence now indicates that internalization of a receptor is not necessarily the endpoint of signaling, but can also be the beginning of the activation of intracellular signaling pathways. Sphingosine-1-phosphate (S1P) receptors, which are ac-tivated by the endogenous phospholipid S1P, belong to the family of GPCRs. Interestingly, there is evidence indi-cating differential intracellular trafficking of one of the S1P receptor subtypes, the S1P1 receptor, upon agonist activa-tion by either S1P or the synthetic agonist FTY720-P. Moreover, the differential effect of FTY720-P on S1P1 re-ceptor regulation has been suggested to be the mecha-nism of action of this drug, which is now in Phase III clini-cal trials for the treatment of multiple sclerosis. It is thus of importance to get a good insight into the regulation of S1P receptors. This review therefore gives a detailed overview about the current state of knowledge on S1P receptor in-ternalization and its functional implications, including some data on nuclear signaling of S1P receptors.

      • SCIESCOPUSKCI등재

        Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

        Park, Soo-Jin,Im, Dong-Soon The Korean Society of Applied Pharmacology 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.1

        Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, $S1P_{1-5}$. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn's disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.

      • SCIESCOPUSKCI등재

        Analysis of a Sphingosine 1-phosphate Receptor $hS1P_3$ in Rat Hepatoma Cells

        Im, Dong-Soon The Korean Society of Pharmacology 2002 The Korean Journal of Physiology & Pharmacology Vol.6 No.3

        To examine intracellular signaling of human $S1P_3\;(hS1P_3),$ a sphingosine 1-phosphate (S1P) receptor in plasma membrane, $hS1P_3$ DNA was transfected into RH7777 rat hepatoma cell line, and the inhibition of forskolin-induced cAMP accumulation and activation of MAP kinases by S1P were tested. In $hS1P_3$ transformants, S1P inhibited forskolin-induced activation of adenylyl cyclase activity by about 80% and activated MAP kinases in dose-dependent and pertussis-toxin (PTX) sensitive manners. In oocytes expressing $hS1P_3$ receptor, S1P evoked $Cl^-$ conductance. These data suggested that PTX-sensitive G proteins are involved in $hS1P_3-mediated$ signaling, especially the positive action of S1P in cell proliferation. The potential advantages of rat hepatoma cells for the research of sphingosine 1-phosphate receptor are discussed.

      • KCI등재

        Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

        ( Soo-jin Park ),( Dong-soon Im ) 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.1

        Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P<sub>1-5</sub>. The molecular iden-tification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn`s disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.

      • KCI우수등재

        Decreased Expression of Sphingosine-1-Phosphate Receptor 1 in the Blood Leukocyte of Rheumatoid Arthritis Patients

        최현석,김경훈,진서훈,김진현,유인설,백승필,하운환,박태원,최수안,육순홍,강성욱,정용우 대한면역학회 2018 Immune Network Vol.18 No.5

        Sphingosine-1-phosphate (S1P) plays an important role in trafficking leukocytes and developing immune disorders including autoimmunity. In the synovium of rheumatoid arthritis (RA) patients, increased expression of S1P was reported, and the interaction between S1P and S1P receptor 1 (S1P1) has been suggested to regulate the expression of inflammatory genes and the proliferation of synovial cells. In this study, we investigated the level of S1P1 mRNA expression in the blood leukocytes of RA patients. In contrast to the previous reports, the expression level of this gene was not correlated to their clinical scores, disease durations and ages. However, S1P1 was transcribed at a significantly lower level in the circulating leukocytes of RA patients when compared to age-, and sex-matched healthy controls. Since these data may suggest the participation of S1P1, further studies are needed to determine the role of this receptor in the pathogenesis of RA.

      • Sphingosine -1 -phosphate (S1P) receptor modulator ameliorates systemic lupus erythematosus via regulation of autoreactive T cell and B cell function

        A Ram LEE,Seon-Young Lee,JeongWon Choi,Kunhee Lee,Sung-Hwan Park,Mi-La Cho 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7

        As circulating autoantibodies and immune complex deposition is a pathological hallmark of systemic lupus erythematosus (SLE), B cell differentiation into plasma cells (PCs) and some T cell subsets functioning as B-cell helpers can be therapeutic target of SLE. Th17 and Treg cell imbalance is involved in the occurrence and development of SLE. Th17 cells and IL-17 cytokine promote autoantibodies from plasma B cell and kidney nephritis. Th17 cells are abundant in the gut because they are education and development in gut. Developmental Th17 cells from gut are migration to systemic organ in inflammatory condition. Fingolimod (FTY720) is mediated by the modulation of sphingosine-1 phosphate (S1P) receptor. Fingolimod phosphate binds to S1P1 receptors on lymphocytes, causing internalization and degradation of the receptors. This reduces S1P–S1P1-dependent egress and migration of lymphocytes from lymph nodes and reduces the recirculation of auto-aggressive T cells via lymph and blood to the target organs. We examined whether the blocks of S1P–S1P1 cell signaling reduce autoreactive T and B cell and lupus disease activity. Oral administration of FTY720 can inhibit the formation of splenic follicles and inflammations in kidney tissues, and also decrease serum levels of anti-dsDNA antibodies. FTY720 altered autoreactive T and B cell subsets inhibition of CD4-CD8- double negative T cells, B220+GL7+ GC B cells and B220–CD138+ PCs occurred. Taken together, FTY720 is therapeutic value on SLE via inhibiting autoreactive T and B cells trafficking to target organ such as kidney.

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