Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties

Lazaridis, Konstantinos N.; Tietz, Pamela S.; Wu, Ting; Kip, Sertac N.; Dawson, Paul A.; LaRusso, Nicholas F.

doi:10.1073/pnas.200325297

Cited by 124 publications

(75 citation statements)

References 24 publications

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“…However, the relative in vivo contribution of these transport activities to basolateral bile acid export is unknown. Several different candidate genes have also been proposed for the ileal basolateral transporter, including the ABC transporter Mrp3 (9, 10) and an alternatively spliced form of the Asbt (8). Unfortunately, their roles in ileal basolateral bile acid transport remain uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…Considering the high flux of bile acids across the ileal enterocyte (1), it is likely that a dedicated basolateral bile acid transporter is required. More recently, additional candidate ileal basolateral bile acid transporters have been proposed, including t-Asbt (8) and the multidrug resistance-associated protein 3 (Mrp3, gene name Abcc3) (9,10). However, their specific roles are uncertain, and the identity of the basolateral bile acid transporter remains a missing link in our understanding of the enterohepatic circulation.…”

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confidence: 99%

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The Heteromeric Organic Solute Transporter α-β, Ostα-Ostβ, Is an Ileal Basolateral Bile Acid Transporter

Dawson

Hubbert

Haywood

et al. 2005

Journal of Biological Chemistry

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349

364

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Bile acids are transported across the ileal enterocyte brush border membrane by the well characterized apical sodium-dependent bile acid transporter (Asbt) Slc10a2; however, the carrier(s) responsible for transporting bile acids across the ileocyte basolateral membrane into the portal circulation have not been fully identified. Transcriptional profiling of wild type and Slc10a2 null mice was employed to identify a new candidate basolateral bile acid carrier, the heteromeric organic solute transporter (Ost)␣-Ost␤. By Northern blot analysis, Ost␣ and Ost␤ mRNA was detected only in mouse kidney and intestine, mirroring the horizontal gradient of expression of Asbt in the gastrointestinal tract. Analysis of Ost␣ and Ost␤ protein expression by immunohistochemistry localized both subunits to the basolateral surface of the mouse ileal enterocyte. The transport properties of Ost␣-Ost␤ were analyzed in stably transfected Madin-Darby canine kidney cells. Coexpression of mouse Ost␣-Ost␤, but not the individual subunits, stimulated Na ؉ -independent bile acid uptake and the apical-to-basolateral transport of taurocholate. In contrast, basolateral-to-apical transport was not affected by Ost␣-Ost␤ expression. Co-expression of Ost␣ and Ost␤ was required to convert the Ost␣ subunit to a mature glycosylated endoglycosidase H-resistant form, suggesting that co-expression facilitates the trafficking of Ost␣ through the Golgi apparatus. Immunolocalization studies showed that co-expression was necessary for plasma membrane expression of both Ost␣ and Ost␤. These results demonstrate that the mouse Ost␣-Ost␤ heteromeric transporter is a basolateral bile acid carrier and may be responsible for bile acid efflux in ileum and other ASBT-expressing tissues.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Heteromeric Organic Solute Transporter α-β, Ostα-Ostβ, Is an Ileal Basolateral Bile Acid Transporter

Dawson

Hubbert

Haywood

et al. 2005

Journal of Biological Chemistry

Self Cite

349

364

View full text Add to dashboard Cite

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“…In 40% of the cases, variant protein sequences are generated by splice alternatives utilizing exons in different reading frames. The use of an exon in two reading frames may result from the use of alternative 5Ј-or 3Ј-splice sites; from the retention of an intron; or, as in the case of DCLK, from the differential inclusion of an exon encoding an odd number of nucleotides (25).…”

Section: Discussionmentioning

confidence: 99%

Alternative Splice Variants of Doublecortin-like Kinase Are Differentially Expressed and Have Different Kinase Activities

Burgess

Reiner

2002

Journal of Biological Chemistry

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Alternative splicing of mRNA transcripts expands the range of protein products from a single gene locus. Several splice variants of DCLK (doublecortin-like kinase) have previously been reported. Here, we report the genomic organization underlying the splice variants of DCLK and examine the expression profile of two splice variants affecting the kinase domain of DCLK and CPG16 (candidate plasticity gene 16), one containing an Arg-rich domain and the other affecting the C terminus of the protein. These splice alternatives were differentially expressed in embryonic and adult brain. Both splice variants disrupted DCLK PEST domains; however, all splice variants remained sensitive to proteolysis by calpain. The adult-specific C-terminal splice variant of DCLK had reduced autophosphorylation activity, but similar kinase activity for myelin basic protein relative to the embryonic splice variant. The splice variant adding an Arg-rich domain gained an autophosphorylation site at Ser-382. Although this protein isoform was expressed mainly in the adult brain, the phosphorylated form was strongly enriched in embryonic brain and adult olfactory bulb, suggesting a possible role in migrating neurons.The majority of neuronal cells in the central nervous system are generated during embryogenesis and persist throughout life without further rounds of division and differentiation. Individual neurons accomplish an array of distinct tasks during their life span, including cellular migration, axon extension and pathfinding, synaptogenesis, and participation in mature nervous system function. It has been suggested that to deal with these diverse demands on cellular function, the repertoire of neuronal gene products is enhanced by alternative splicing and RNA editing. Following the description of differential RNA processing of the calcitonin gene (1), alternative splice forms of many gene products have been detected in the central nervous system (2, 3). Doublecortin-like kinase (DCLK) 1 is a serine-threonine kinase expressed in the central nervous system. The N-terminal domain of DCLK is very similar to the doublecortin protein and mediates microtubule localization (4 -6). The C-terminal kinase domain of DCLK resembles members of the family of calcium/calmodulin-dependent protein kinases, but lacks a canonical calmodulin-binding site (7). The human gene was named DCAMKL1 (doublecortin-and Ca 2ϩ /calmodulindependent protein kinase-like protein-1) (8); however, biochemical evidence does not indicate that calcium/calmodulin modulates kinase activity (7).The DCLK locus gives rise to several transcripts through differential splicing and use of alternative promoters (see Fig. 1). The DCL product includes the doublecortin domain, but lacks the kinase domain. DCLK Rϩ is a full-length transcript embracing both doublecortin and kinase domains and includes an additional 16 amino acids enriched in arginine residues (the Arg-rich domain), between the doublecortin and kinase domains (9). Two splice variants affecting the final coding exon of DCLK hav...

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“…t-Asbt was localised to the basolateral plasma membrane of cholangiocytes and was shown to mediate bile acid efflux (Lazaridis et al 2000). The physiological role of Asbt expression in cholangiocytes is not clear.…”

Section: Functional Properties and Expression Patterns Of The Individmentioning

confidence: 99%

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

Geyer

Wilke

Petzinger

2006

Naunyn Schmied Arch Pharmacol

161

138

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The solute carrier family 10 (SLC10) comprises two sodium-dependent bile acid transporters, i.e. the Na + / taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). These carriers are essentially involved in the maintenance of the enterohepatic circulation of bile acids mediating the first step of active bile acid transport through the membrane barriers in the liver (NTCP) and intestine (ASBT). Recently, four new members of the SLC10 family were described and referred to as P3 (SLC10A3), P4 (SLC10A4), P5 (SLC10A5) and sodium-dependent organic anion transporter (SOAT; SLC10A6). Experimental data supporting carrier function of P3, P4, and P5 is currently not available. However, as demonstrated for SOAT, not all members of the SLC10 family are bile acid transporters. SOAT specifically transports steroid sulfates such as oestrone-3-sulfate and dehydroepiandrosterone sulfate in a sodium-dependent manner, and is considered to play an important role for the cellular delivery of these prohormones in testes, placenta, adrenal gland and probably other peripheral tissues. ASBT and SOAT are the most homologous members of the SLC10 family, with high sequence similarity (∼70%) and almost identical gene structures. Phylogenetic analyses of the SLC10 family revealed that ASBT and SOAT genes emerged from a common ancestor gene. Structure-activity relationships of NTCP, ASBT and SOAT are discussed at the amino acid sequence level.Based on the high structural homology between ASBT and SOAT, pharmacological inhibitors of the ASBT, which are currently being tested in clinical trials for cholesterollowering therapy, should be evaluated for their crossreactivity with SOAT.

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Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties

Cited by 124 publications

References 24 publications

The Heteromeric Organic Solute Transporter α-β, Ostα-Ostβ, Is an Ileal Basolateral Bile Acid Transporter

The Heteromeric Organic Solute Transporter α-β, Ostα-Ostβ, Is an Ileal Basolateral Bile Acid Transporter

Alternative Splice Variants of Doublecortin-like Kinase Are Differentially Expressed and Have Different Kinase Activities

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

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