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Titolo:
Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C
Autore:
Lu, R; Chan, BS; Schuster, VL;
Indirizzi:
Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA Yeshiva Univ Albert Einstein Coll Med Bronx NY USA 10461 nx, NY 10461 USA Yeshiva Univ Albert Einstein Coll Med, Dept Physiol, Bronx, NY 10461 USA Yeshiva Univ Albert Einstein Coll Med Bronx NY USA 10461 nx, NY 10461 USA Yeshiva Univ Albert Einstein Coll Med, Dept Biophys, Bronx, NY 10461 USA Yeshiva Univ Albert Einstein Coll Med Bronx NY USA 10461 nx, NY 10461 USA
Titolo Testata:
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
fascicolo: 2, volume: 45, anno: 1999,
pagine: F295 - F303
SICI:
0363-6127(199902)45:2<F295:COTHKP>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
ORGANIC ANION TRANSPORTER; RENAL PROXIMAL TUBULE; MEMBRANE-VESICLES; PROSTAGLANDIN TRANSPORTER; PARA-AMINOHIPPURATE; CATION TRANSPORTER; EXPRESSION CLONING; RAT-KIDNEY; SECRETION; MECHANISMS;
Keywords:
carrier proteins; biological transport; organic anion transport; hormonal control; renal secretion; p-aminohippurate; phorbol ester;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Schuster, VL Div Renal, Ullmann 617,1300 Morris Pk Ave, Bronx, NY 10461 USA Div Renal Ullmann 617,1300 Morris Pk Ave Bronx NY USA 10461 A
Citazione:
R. Lu et al., "Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C", AM J P-REN, 45(2), 1999, pp. F295-F303

Abstract

Conserved from fish to mammals, renal proximal tubule organic anion secretion plays an important role in drug and xenobiotic elimination. Studies with the model substrate p-aminohippurate (PAH) have suggested that a basolateral PAH/alpha-ketoglutarate exchanger imports diverse organic substrates into the proximal tubule prior to apical secretion. cDNAs encoding PAH transporters have been cloned recently from rat and flounder. Here we report the cloning of a highly similar human PAH transporter (hPAHT) from human kidney. By Northern blot analysis and EST database searching, hPAHT mRNA was detected in kidney and brain. PCR-based monochromosomal somatic cell hybrid mapping placed the hPAHT gene on chromosome 11. When expressed transiently in vitro, hPAHT catalyzed time-dependent and saturable [H-3]PAH uptake (K-m ofsimilar to 5 mu M). Preincubation with unlabeled ol-ketoglutaric or with glutaric acid stimulated tracer PAH uptake, and preincubation with unlabeledPAH stimulated tracer alpha-ketoglutarate uptake, results that are consistent with PAH/alpha-ketoglutarate exchange. Several structurally diverse organic anions cis-inhibited PAH uptake. Like rat OAT1 organic anion transporter, hPAHT was inhibited by furosemide, indomethacin, probenecid, and alpha-ketoglutarate. Unlike OAT1, hPAHT was not inhibited by prostaglandins or methotrexate (MTX). Moreover, tracer PGE(2) and MTX were not transported, indicating that the substrate specificity for transport by hPAHT is not broad. PAH uptake was inhibited by phorbol 12-myristate 13-acetate (PMA) in a dose- and time-dependent fashion, but not by the inactive 4 alpha-phorbol-12,13 didecanoate. PMA-induced inhibition was blocked by staurosporine. Thus the protein kinase C-mediated inhibition of basolateral organic anion entry previously reported in intact tubules is likely due, at least in part, to direct modulation of the PAH/alpha-ketoglutarate exchanger.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/07/20 alle ore 01:15:25