ライフサイエンスコーパス: OAT1

1 OAT1 and OAT3 localized to basolateral membranes of nonp

2 Organic anion transporter 1 (OAT1) mediates the body disposition of a diverse array o

3 Organic anion transporter 1 (OAT1), originally identified as NKT, has physiological p

4 of ligands with organic anion transporter 1 (OAT1).

5 Notably, organic anion transporter-1 (OAT1) knockout mice expressed a similar pattern of reduc

6 Organic anion transporter-1 (OAT1) mediates the body disposition of a diverse array o

7 Organic anion transporter-1 (OAT1) mediates the body's disposition of a diverse array

8 atory drugs) is organic anion transporter-1 (OAT1), originally identified as NKT.

9 following transporters: GLUT-1; MCT 1 and 2; OAT1; Oatp1; mdr 1a and 1b; MRP 1 and 5; beta-alanine, s

10 sma membrane, and PKC activation accelerated OAT1 internalization without affecting OAT1 recycling.

11 rated OAT1 internalization without affecting OAT1 recycling.

12 Although OAT1 function (uptake in oat3(-/-) tissue) was confined

13 d partially reversed by p-aminohippurate (an OAT1 substrate).

14 ffects were fully reversed by probenecid (an OAT1 inhibitor) and partially reversed by p-aminohippura

15 by PKCzeta, subsequently confirmed using an OAT1-specific substrate, adefovir.

16 enous compounds enabling construction of an "OAT1-centered metabolic interaction network." Pathway an

17 ll as transcriptomic data from wild-type and OAT1 knock-out animals, resulting in the implication of

18 sts that OAT1 ubiquitination proceeds before OAT1 internalization.

19 sue assays demonstrated interactions between OAT1 and key intermediates in these metabolic pathways,

20 ive mutant of dynamin-2, a maneuver blocking OAT1 internalization, which suggests that OAT1 ubiquitin

21 preserved kidney structure and function, but OAT1-transported 2OGA was not protective, suggesting tha

22 ute activation of PKC significantly enhances OAT1 ubiquitination both in vitro and ex vivo.

23 s OAT1 activity by altering already existent OAT1 trafficking, and (iii) OAT1 internalization occurs

24 the organic anion transporter (OAT) family: OAT1 (SLC22A6, originally NKT) and OAT3 (SLC22A8).

25 Drugs may alter metabolism by competing for OAT1 binding of metabolites.

26 NA (RT-PCR) and protein (immunoblotting) for OAT1, OAT3, NaDC3, and MRP4 were detected in extracts of

27 tion at individual sites is not required for OAT1 function, and 3) glycosylation plays an important r

28 hat PKC isoform PKCalpha was responsible for OAT1 ubiquitination.

29 We demonstrate a key in vivo role for OAT1 and/or OAT3 in the handling of over 35 uremic toxin

30 ent analysis indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan

31 ork is also consistent with a major role for OAT1 in modulating metabolic and signaling pathways invo

32 These results indicate a critical role for OAT1 in the functioning of the classical pathway.

33 ee-dimensional model was generated for human OAT1 (hOAT1) based on fold recognition to the crystal st

34 ngs demonstrated for the first time that (i) OAT1 constitutively traffics between plasma membrane and

35 already existent OAT1 trafficking, and (iii) OAT1 internalization occurs partly through a dynamin- an

36 sts, and beta-lactam antibiotics) to inhibit OAT1 expressed in Chinese hamster ovary cells.

37 ctivation of protein kinase C (PKC) inhibits OAT1 activity by promoting ubiquitination of the transpo

38 ctivation of protein kinase C (PKC) inhibits OAT1 activity by reducing OAT1 cell-surface expression t

39 c drug and organic anion transporters (OATs) OAT1 (SLC22a6) and OAT3 (SLC22a8).

40 the present study implicate the activity of OAT1 in the uptake and toxicity of Hg (when in the form

41 We have now generated a colony of OAT1 knock-out mice, permitting elucidation of the role

42 To investigate the contribution of OAT1 and OAT3 in various nephron segments, the OAT-selec

43 ies; therefore, the relative contribution of OAT1 has remained unclear.

44 opathy demonstrated lower gene expression of OAT1 and OAT3.

45 ion and characterization of glycosylation of OAT1 and may provide important insights into the structu

46 al differences in the relative importance of OAT1 and OAT3 in antiviral handling in developing and ma

47 nock-out mice, suggesting the involvement of OAT1 in their renal secretion.

48 t of extracellular alphaKG on the potency of OAT1 inhibition should be considered when assessing drug

49 ucially involved in substrate recognition of OAT1, 2) glycosylation at individual sites is not requir

50 Therefore, understanding the regulation of OAT1 has profound clinical significance.

51 novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic

52 mice, permitting elucidation of the role of OAT1 in the context of these other potentially functiona

53 To directly address the role of OAT1 ubiquitination, we then generated two OAT1 mutants,

54 This gives a picture of the in vivo roles of OAT1 and OAT3 in the regulation of the uremic solutes an

55 We therefore examined the potential roles of OAT1 in metabolic pathways using Recon 1, a functionally

56 mentally validated, confidence ranked set of OAT1-interacting endogenous compounds enabling construct

57 might represent physiological substrates of OAT1.

58 cy are potential transportable substrates of OAT1.

59 plays an important role in the targeting of OAT1 onto the plasma membrane.

60 We further showed that treatment of OAT1-expressing cells with concanavalin A, depletion of

61 troscopy has revealed that ubiquitination of OAT1 consists of polyubiquitin chains, primarily through

62 e C (PKC) inhibits OAT1 activity by reducing OAT1 cell-surface expression through accelerating its in

63 antly blocked constitutive and PKC-regulated OAT1 internalization.

64 biquitination is essential for PKC-regulated OAT1 trafficking.

65 315 play a synergistic role in PKC-regulated OAT1 ubiquitination, trafficking, and transport activity

66 ndosomes, (ii) PKC activation down-regulates OAT1 activity by altering already existent OAT1 traffick

67 nstrate that PKCzeta activation up-regulates OAT1 and OAT3 function, and that protein-protein interac

68 Transport of the shared OAT1/OAT3 substrate, rho-aminohippurate, behaved similar

69 lyubiquitin chains, abolishes PKC-stimulated OAT1 ubiquitination and internalization.

70 her show that ubiquitination of cell-surface OAT1 increases in cells transfected with dominant negati

71 We previously demonstrate that OAT1 activity was down-regulated by activation of protei

72 We previously established that OAT1 constitutively internalizes from and recycles back

73 We had previously established that OAT1 undergoes constitutive internalization from and rec

74 The fact that OAT1 can affect many systemic biological pathways sugges

75 This observation raises the possibility that OAT1 helps regulate broader metabolic activities.

76 We finally showed that OAT1 colocalized with transferrin, a marker for clathrin

77 In the current study, we showed that OAT1 constitutively internalized from and recycled back

78 ed metabolomics in knockouts have shown that OAT1 mediates the secretion or reabsorption of many impo

79 This suggested that OAT1 activity was also modified by PKCzeta, subsequently

80 ng OAT1 internalization, which suggests that OAT1 ubiquitination proceeds before OAT1 internalization

81 s and pathway analysis support the view that OAT1 plays a greater role in kidney proximal tubule meta

82 oxicity of this conjugate was reduced by the OAT1-exchangeable dicarboxylates alpha-ketoglutarate, gl

83 s with OAT1 highlights the complexity of the OAT1 ligand-binding surface.

84 predictions for metabolic pathways linked to OAT1-related transport.

85 (OCT2 and OCT3), organic anion transporter (OAT1), and monoamine transporters were also inhibited by

86 The organic anion transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) have similar substrate

87 The organic anion transporters OAT1 (SLC22A6, originally identified by us as NKT) and O

88 f OAT1 ubiquitination, we then generated two OAT1 mutants, each having multiple lysines (K) simultane

89 s that some of these compounds interact with OAT1 in vitro.

90 cellular alphaKG on ligand interactions with OAT1 highlights the complexity of the OAT1 ligand-bindin