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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

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 K_m and a decrease in V_max. 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 K_m 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

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