Folate Receptors And Therapeutic Applications

The folate receptors (FRs) are a family of proteins coded by genes located on chromosome 11 at 11q13 telomeric to Cyclin DI. There are now four members: alpha, beta, gamma, and delta. The first two isoforms are the best studied, and they are targets for both pharmacological and immunotherapies. There is little known about the last two isoforms relative to folate homeostasis. The first two are both glycosylphosphatidylinositol-linked proteins, although soluble forms in plasma and milk also exist. FR alpha is overexpressed by many carcinomas. It is the most completely studied isoform, and it has been the model for receptor-mediated folate uptake by a process named "potocytosis." To mediate folate uptake or transcytosis through epithelia, the FR appears to work in tandem with the recently described proton-coupled folate transporter (PCFT). FR beta is expressed on activated macrophages, and it is being targeted for therapy of patients with autoimmune diseases. The function of the FR, as well as regulation of its cycling in the lipid rafts on the cell membrane, is the subject of this review. The clinical significance of abnormal, missing, or soluble FR levels and associated autoantibodies will also be discussed in light of embryopathies and neurocognitive dysfunction.