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Am J Physiol Cell Physiol (September 26, 2007). doi:10.1152/ajpcell.00202.2007
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Submitted on May 16, 2007
Accepted on September 19, 2007

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

Andong Qiu1, Sang Hee Min2, Michaela Jansen3, Usha Malhotra2, Eugenia Tsai1, Diane C. Cabelof4, Larry H. Matherly5, Rongbao Zhao1, Myles H. Akabas6, and I. David Goldman1*

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

* To whom correspondence should be addressed. E-mail: igoldman{at}aecom.yu.edu.

This laboratory recently identified a human gene that encodes a novel folate transporter (HsPCFT; SLC46A1) required for intestinal folate absorption. This study focuses on mouse and rat PCFTs (MmPCFT and 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 N- and C- 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 the rodent PCFT proteins likely contain twelve transmembrane domains. Transport of [3H]folates was optimal at pH 5.5, decreasing with increasing pH due to an increase in Km and 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 Kms 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 duodenum, proximal jejunum, liver, and kidney with lesser expression in brain and other tissues. MmPCFT protein was localized to the apical brush-border membrane of duodenum and proximal jejunum. MmPCFT mRNA levels increased ~13 fold in the proximal small intestine in mice fed a folate-deficient vesus a folate-replete diet, consistent with the critical role that PCFT plays in intestinal folate absorption.




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