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Am J Physiol Cell Physiol 293: C1669-C1678, 2007. First published September 26, 2007; doi:10.1152/ajpcell.00202.2007
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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction

Andong Qiu,1,2 Sang Hee Min,1 Michaela Jansen,3 Usha Malhotra,1 Eugenia Tsai,1,2 Diane C. Cabelof,4 Larry H. Matherly,4,5 Rongbao Zhao,1,2 Myles H. Akabas,1,3 and I. David Goldman1,2

Departments of 1Medicine, 2Molecular Pharmacology, and 3Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York; 4Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and 5Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan

Submitted 16 May 2007 ; accepted in final form 19 September 2007

This laboratory recently identified a human gene that encodes a novel folate transporter [Homo sapiens proton-coupled folate transporter (HsPCFT); SLC46A1] required for intestinal folate absorption. This study focused on mouse (Mus musculus) PCFT (MmPCFT) and rat (Rattus norvegicus) PCFT (RnPCFT) and addresses their secondary structure, specificity, tissue expression, and regulation by dietary folates. Both rodent PCFT proteins traffic to the cell membrane with the NH2- and COOH-termini accessible to antibodies targeted to these domains only in permeabilized HeLa cells. This, together with computer-based topological analyses, is consistent with a model in which rodent PCFT proteins likely contain 12 transmembrane domains. Transport of [3H]folates was optimal at pH 5.5 and decreased with increasing pH due to an increase in Km and a decrease in Vmax. At pH 7.0, folic acid and methotrexate influx was negligible, but there was residual (6S)5-methyltetrahydrofolate transport. Uptake of folates in PCFT-injected Xenopus oocytes was electrogenic and pH dependent. Folic acid influx Km values of MmPCFT and RnPCFT, assessed electrophysiologically, were 0.7 and 0.3 µM at pH 5.5 and 1.1 and 0.8 µM at pH 6.5, respectively. Rodent PCFTs were highly specific for monoglutamyl but not polyglutamyl methotrexate. MmPCFT mRNA was highly expressed in the duodenum, proximal jejunum, liver, and kidney with lesser expression in the brain and other tissues. MmPCFT protein was localized to the apical brush-border membrane of the duodenum and proximal jejunum. MmPCFT mRNA levels increased ~13-fold in the proximal small intestine in mice fed a folate-deficient vesus folate-replete diet, consistent with the critical role that PCFT plays in intestinal folate absorption.

intestinal folate absorption; proton-coupled folate transporters; heme carrier protein-1; hereditary folate malabsorption


Address for reprint requests and other correspondence: I. D. Goldman, Depts. of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Cancer Research Center, Chanin 2, Bronx, NY 10461 (e-mail: igoldman{at}aecom.yu.edu)




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