Regulation by protein kinase C of organic anion transport driven by rat organic anion transporter 3 (rOAT3)

Life Sciences ◽  
2000 ◽  
Vol 67 (9) ◽  
pp. 1087-1093 ◽  
Author(s):  
Michio Takeda ◽  
Takashi Sekine ◽  
Hitoshi Endou
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transporter ◽  
Organic Anion Transport ◽  
Kinase C ◽  
Anion Transporter ◽  
Organic Anion Transporter 3

scholarly journals Nedd4-2 but not Nedd4-1 is critical for protein kinase C-regulated ubiquitination, expression, and transport activity of human organic anion transporter 1

2016 ◽  
Vol 310 (9) ◽  
pp. F821-F831 ◽  
Author(s):  
Da Xu ◽  
Haoxun Wang ◽  
Qiang Zhang ◽  
Guofeng You
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Surface ◽  
Organic Anion ◽  
The Body ◽  
Organic Anion Transporter ◽  
Transport Activity ◽  
Kinase C ◽  
Anion Transporter ◽  
In Cells

Human organic anion transporter 1 (hOAT1) expressed at the membrane of the kidney proximal tubule cells mediates the body disposition of a diverse array of clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and antiinflammatories. Therefore, understanding the regulation of hOAT1 will provide significant insights into kidney function and dysfunction. We previously established that hOAT1 transport activity is inhibited by activation of protein kinase C (PKC) through accelerating hOAT1 internalization from cell surface into intracellular endosomes and subsequent degradation. We further established that PKC-induced hOAT1 ubiquitination is an important step preceding hOAT1 internalization. In the current study, we identified two closely related E3 ubiquitin ligases, neural precursor cell expressed, developmentally downregulated 4-1 and 4-2 (Nedd4-1 and Nedd4-2), as important regulators for hOAT1: overexpression of Nedd4-1 or Nedd4-2 enhanced hOAT1 ubiquitination, reduced the hOAT1 amount at the cell surface, and suppressed hOAT1 transport activity. In further exploring the relationship among PKC, Nedd4-1, and Nedd4-2, we discovered that PKC-dependent changes in hOAT1 ubiquitination, expression, and transport activity were significantly blocked in cells transfected with the ligase-dead mutant of Nedd4-2 (Nedd4-2/C821A) or with Nedd4-2-specific siRNA to knockdown endogenous Nedd4-2 but not in cells transfected with the ligase-dead mutant of Nedd4-1 (Nedd4-1/C867S) or with Nedd4-1-specific siRNA to knockdown endogenous Nedd4-1. In conclusion, this is the first demonstration that both Nedd4-1 and Nedd4-2 are important regulators for hOAT1 ubiquitination, expression, and function. Yet they play distinct roles, as Nedd4-2 but not Nedd4-1 is a critical mediator for PKC-regulated hOAT1 ubiquitination, expression, and transport activity.

scholarly journals Hepatocanalicular organic-anion transport is regulated by protein kinase C

1991 ◽  
Vol 278 (3) ◽  
pp. 637-641 ◽  
Author(s):  
H Roelofsen ◽  
R Ottenhoff ◽  
R P J Oude Elferink ◽  
P L M Jansen
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Organic Anion ◽  
Phosphodiesterase Inhibitor ◽  
Second Messenger ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Kinase C ◽  
Transport Assay ◽  
Messenger System

In order to investigate the regulation of canalicular organic-anion transport, we used a hepatocyte transport assay in which canalicular secretion of a model organic anion, dinitrophenyl-glutathione (GS-DNP), was measured in the presence of stimulators and inhibitors of the Ca2+/protein kinase C (PKC) second-messenger system and of the cyclic AMP (cAMP) second-messenger system. Vasopressin (24 nM) and the phorbol ester phorbol 12-myristate 13-acetate (1 microgram/ml), both stimulators of PKC, stimulated GS-DNP efflux by 65 +/- 36% and 55 +/- 28% respectively, whereas staurosporine (10 microM), an inhibitor of PKC, inhibited efflux by 53 +/- 13%. Glucagon and forskolin, both stimulators of the cAMP second-messenger system, as well as the cAMP analogue dibutyryl cAMP and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, did not significantly influence the GS-DNP efflux. It can be concluded that canalicular organic-anion transport in hepatocytes is either directly or indirectly regulated by PKC.

scholarly journals Regulation of mOAT-mediated Organic Anion Transport by Okadaic Acid and Protein Kinase C in LLC-PK1Cells

2000 ◽  
Vol 275 (14) ◽  
pp. 10278-10284 ◽  
Author(s):  
Guofeng You ◽  
Kogo Kuze ◽  
Ronald A. Kohanski ◽  
Kurt Amsler ◽  
Scott Henderson
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Okadaic Acid ◽  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Kinase C

scholarly journals Impaired Organic Anion Transport in Kidney and Choroid Plexus of Organic Anion Transporter 3 (Oat3(Slc22a8)) Knockout Mice

2002 ◽  
Vol 277 (30) ◽  
pp. 26934-26943 ◽  
Author(s):  
Douglas H. Sweet ◽  
David S. Miller ◽  
John B. Pritchard ◽  
Yuko Fujiwara ◽  
David R. Beier ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Knockout Mice ◽  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transporter ◽  
Organic Anion Transport ◽  
Anion Transporter ◽  
Organic Anion Transporter 3

Organic anion transport in choroid plexus from wild-type and organic anion transporter 3 (Slc22a8)-null mice

2004 ◽  
Vol 286 (5) ◽  
pp. F972-F978 ◽  
Author(s):  
Destiny Sykes ◽  
Douglas H. Sweet ◽  
Simon Lowes ◽  
Sanjay K. Nigam ◽  
John B. Pritchard ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transporter ◽  
Null Mouse ◽  
Organic Anion Transport ◽  
Wild Type ◽  
Estrone Sulfate ◽  
Anion Transporter ◽  
Organic Anion Transporter 3

The choroid plexus actively transports endogenous, xenobiotic, and therapeutic compounds from cerebrospinal fluid to blood, thereby limiting their exposure to the central nervous system (CNS). Establishing the mechanisms responsible for this transport is critical to our understanding of basic choroid plexus physiology and will likely impact drug targeting to the CNS. We recently generated an organic anion transporter 3- (Oat3)-null mouse, which exhibited loss of PAH, estrone sulfate, and taurocholate transport in kidney and of fluorescein (FL) transport in choroid plexus. Here, we measured the uptake of four Oat3 substrates by choroid plexus from wild-type and Oat3-null mice to establish 1) the contribution of Oat3 to the apical uptake of each substrate and 2) the Na dependence of transport by Oat3 in the intact tissue. Mediated transport of PAH and FL was essentially abolished in tissue from Oat3-null mice. In contrast, only a 33% reduction in estrone sulfate uptake was observed in tissue from Oat3-null mice and, surprisingly, no reduction in taurocholate uptake could be detected. For PAH, FL, and estrone sulfate, all Oat3-mediated transport was Na dependent. However, estrone sulfate and taurocholate also exhibited additional mediated and Na-dependent components of uptake that were not attributed to Oat3, demonstrating the complexity of organic anion transport in this tissue and the need for further examination of expressed transporters and their energetics.

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