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Protein 4.1R is Involved in the Transport of 5‐Aminolevulinic Acid by Interaction with GATs in MEF Cells

5‐aminolevulinic acid (5‐ALA)‐based photodynamic therapy (PDT) has been successfully used in the treatment of cancers. However, the mechanism of 5‐ALA transportation into cancer cells is still not fully elucidated. Previous studies have confirmed that the efficiency of 5‐ALA‐PDT could be affected by the membrane skeleton protein 4.1R. In this study, we investigated the role of 4.1R in the transport of 5‐ALA into cells. Wild‐type (4.1R+/+) and 4.1R gene knockout (4.1R−/−) mouse embryonic fibroblast (MEF) cells were incubated with 1 mm 5‐ALA and different concentrations of specific inhibitors of GABA transporters GAT (1‐3). Our results showed that the inhibition of GAT1 and GAT2 in particular markedly attenuated the intracellular PpIX production, reactive oxygen species (ROS) level and 5‐ALA‐induced photodamage. However, the inhibition of GAT3 did not show such effects. Further research showed that 4.1R−/− MEF cells had a lower expression of GAT1 and GAT2 than 4.1R+/+ MEF cells. Additionally, 4.1R directly bound to GAT1 and GAT2. Taken together, GAT1 and GAT2 transporters are involved in the uptake of 5‐ALA in MEF cells. 4.1R plays an important role in transporting 5‐ALA into cells via at least partly interaction with GAT1 and GAT2 transporters in 5‐ALA‐PDT.