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1 Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
* To whom correspondence should be addressed. E-mail: rzhao{at}aecom.yu.edu.
Intestinal folate transport has been well characterized and rat small intestinal epithelial cells (IEC-6 cells) have been employed as a model system for the study of this process on the cellular level. The major intestinal folate transport activity has a low pH optimum and the current paradigm is that this process is mediated by the reduced folate carrier (RFC) despite the fact that this carrier has a neutral pH optimum in leukemia cells. The current study addresses the question as to whether constitutive low-pH folate transport activity in IEC-6 cells is mediated by RFC. Two independent IEC-6 sublines, IEC-6/A4 and IEC-6/PT1, were generated by chemical mutagenesis followed by selective pressure with antifolates. In IEC-6/A4 cells, a premature stop resulted in truncation of RFC at glutamine 420. A GFP fusion with the truncated protein was not stable. In IEC-6/PT1 cells, serine135 was deleted and this alteration resulted in failure of localization of the GFP fusion protein in the plasma membrane. In both cell lines, methotrexate influx at neutral pH was markedly decreased as compared to wild-type IEC-6 cells, but methotrexate influx at pH 5.5 was not depressed. Transient transfection of the GFP-mutated RFC constructs into RFC-null HeLa cells confirmed their lack of transport function. These results indicate that in IEC-6 cells, folate transport at neutral pH is mediated predominantly by RFC; however, the folate transport activity at pH 5.5 is RFC-independent. Hence, constitutive folate transport activity with a low-pH optimum in this intestinal cell model is mediated by a process entirely distinct from RFC.
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