Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force (     , ). Involved in the intestinal absorption of folates at the brush-border membrane of the proximal jejunum, and the transport from blood to cerebrospinal fluid across the choroid plexus (    ). Functions at acidic pH via alternate outward- and inward-open conformation states (, ). Protonation of residues in the outward open state primes the protein for transport . Binding of folate promotes breaking of salt bridge network and subsequent closure of the extracellular gate, leading to the inward-open state and release of protons and folate . Also able to transport antifolate drugs, such as methotrexate and pemetrexed, which are established treatments for cancer and autoimmune diseases (   , ). Involved in FOLR1-mediated endocytosis by serving as a route of export of folates from acidified endosomes . Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine . Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells . Hence, participates in the trafficking of heme and increases intracellular iron content .
Inactive isoform which is not able to mediate proton-coupled folate transport.
Subcellular locations: Cell membrane, Apical cell membrane, Basolateral cell membrane, Endosome membrane, Cytoplasm
Localizes to the apical membrane of intestinal cells in iron-deficient cells, while it resides in the cytoplasm in iron-replete cells (By similarity). Localizes to the basolateral membrane of choroid plexus .
Expressed at highest level in the upper half of the small intestine (duodenum and jejunum), expression decreases downwardly in the subsequent quarter and is undetectable in the last quarter (the lowest ileum) (, ). Also expressed in kidney, liver, placenta, spleen, retina and retinal pigment epithelium (, ). Lower levels found in testis . Very low levels in brain, lung, stomach, heart and muscle .