Hepatocyte Basolateral Membrane Organic Anion Transporters

Choi, Jo H.; Murray, John W.; Wolkoff, Allan W.

doi:10.1002/9780470747919.ch21

The Liver 2009

DOI: 10.1002/9780470747919.ch21

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Hepatocyte Basolateral Membrane Organic Anion Transporters

Jo H. Choi

John W. Murray

Allan W. Wolkoff

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Cited by 2 publications

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“…The initial member of this family was identified and cloned in a Xenopus laevis oocyte expression system on the basis of its ability to mediate transport of the organic anion sulfobromophthalein (20,21). Subsequently, Ͼ20 additional members of the oatp family have been described (17,18); 4 of these are expressed in the liver (7). The originally identified oatp is now termed oatp1a1.…”

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confidence: 99%

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PDZK1 binding and serine phosphorylation regulate subcellular trafficking of organic anion transport protein 1a1

Choi

Murray

Wolkoff

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Although perturbation of organic anion transport protein (oatp) cell surface expression can result in drug toxicity, little is known regarding mechanisms regulating its subcellular distribution. Many members of the oatp family, including oatp1a1, have a COOH-terminal PDZ consensus binding motif that interacts with PDZK1, while serines upstream of this site (S634 and S635) can be phosphorylated. Using oatp1a1 as a prototypical member of the oatp family, we prepared plasmids in which these serines were mutated to glutamic acid [E634E635 (oatp1a1(EE)), phosphomimetic] or alanine [A634A635 (oatp1a1(AA)), nonphosphorylatable]. Distribution of oatp1a1(AA) and oatp1a1(EE) was largely intracellular in transfected human embryonic kidney (HEK) 293T cells. Cotransfection with a plasmid encoding PDZK1 revealed that oatp1a1(AA) was now expressed largely on the cell surface, while oatp1a1(EE) remained intracellular. To quantify these changes, studies were performed in HuH7 cells stably transfected with these oatp1a1 plasmids. These cells endogenously express PDZK1. Surface biotinylation at 4°C followed by shift to 37°C showed that oatp1a1(EE) internalizes quickly compared with oatp1a1(AA). To examine a physiological role for phosphorylation in oatp1a1 subcellular distribution, studies were performed in rat hepatocytes exposed to extracellular ATP, a condition that stimulates serine phosphorylation of oatp1a1 via activity of a purinergic receptor. Internalization of oatp1a1 under these conditions was rapid. Thus, although PDZK1 binding is required for optimal cell surface expression of oatp1a1, phosphorylation provides a mechanism for fast regulation of the distribution of oatp1a1 between the cell surface and intracellular vesicular pools. Identification of the proteins and motor molecules that mediate these trafficking events represents an important area for future study.

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confidence: 99%

“…It was also recognized that members of the oatp family have a highly conserved PDZ consensus binding site at the COOH terminus (7,41). In most of these cases, the terminal four amino acids that define this binding domain are KTKL, and previous studies with oatp1a1 showed that this sequence mediates binding to PDZK1 (41).…”

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confidence: 99%

PDZK1 binding and serine phosphorylation regulate subcellular trafficking of organic anion transport protein 1a1

Choi

Murray

Wolkoff

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Oatp1a1 Requires PDZK1 to Traffic to the Plasma Membrane by Selective Recruitment of Microtubule-Based Motor Proteins

2013

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Previous studies identified a family of organic anion transport proteins (OATPs), many of which have C-terminal PDZ binding consensus sequences. In particular, the C-terminal four amino acids of Oatp1a1, a transporter on rat and mouse hepatocytes, comprise a consensus binding site for PDZK1. In PDZK1 knockout mice and in transfected cells where PDZK1 expression was knocked down, Oatp1a1 accumulates in intracellular vesicles. The present study tests the hypothesis that Oatp1a1 traffics to and from the cell surface in vesicles along microtubules, and that PDZK1 guides recruitment of specific motors to these vesicles. Oatp1a1-containing vesicles were prepared from wild-type and PDZK1 knockout mice. As seen by immunofluorescence, kinesin-1, a microtubule plus-end directed motor, was largely associated with vesicles from wildtype mouse liver, whereas dynein, a minus-end directed motor, was largely associated with vesicles from PDZK1 knockout mouse liver. Quantification of motility on directionally marked microtubules following addition of 50 mM ATP showed that wild-type vesicles moved equally toward the plus and minus ends whereas PDZK1 knockout vesicles moved predominantly toward the minus end, consistent with net movement toward the cell interior. These studies provide a novel mechanism by which PDZK1 regulates intracellular trafficking of Oatp1a1 by recruiting specific motors to Oatp1a1-containing vesicles. In the absence of PDZK1, Oatp1a1-containing vesicles cannot recruit kinesin-1 and associate with dynein as a predominant minus-end directed motor. Whether this is a result of direct interaction of the Oatp1a1 cytoplasmic domain with dynein or with a dynein-containing protein complex remains to be established.

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Hepatocyte Basolateral Membrane Organic Anion Transporters

Cited by 2 publications

References 130 publications

PDZK1 binding and serine phosphorylation regulate subcellular trafficking of organic anion transport protein 1a1

PDZK1 binding and serine phosphorylation regulate subcellular trafficking of organic anion transport protein 1a1

Oatp1a1 Requires PDZK1 to Traffic to the Plasma Membrane by Selective Recruitment of Microtubule-Based Motor Proteins

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