title: Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene.
abstract: The choroid plexus (CP) forms the blood-cerebrospinal fluid (CSF) barrier and protects the brain from circulating metabolites, drugs, and toxins. The plasma membrane monoamine transporter (PMAT, SLC29A4) is a new polyspecific organic cation transporter that transports a wide variety of organic cations including biogenic amines, cationic drugs, and neurotoxins. PMAT is known to be expressed in the CP, but its specific role in CP transport of organic cations has not been clearly defined. Here we showed that PMAT transcript is highly expressed in human and mouse CPs, whereas transcripts of other functionally related transporters are minimally expressed in the CPs. Immunofluorescence staining further revealed that PMAT protein is localized to the apical (CSF-facing) membrane of the CP epithelium, consistent with a role of transporting organic cations from the CSF into CP epithelial cells. To further evaluate the role of PMAT in the CP, mice with targeted deletion of the Slc29a4 gene were generated and validated. Although Pmat(-/-) mice showed no overt abnormalities, the uptake of monoamines and the neurotoxin 1-methyl-4-phenylpyridinium was significantly reduced in CP tissues isolated from the knock-out mice. Together, our data demonstrated that PMAT is a major transporter for CP uptake of bioactive amines and xenobiotic cations. By removing its substrates from the CSF, PMAT may play an important role in protecting the brain from cationic neurotoxins and other potentially toxic organic cations.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Haichuan
authors.initials: H
authors.lastname: Duan
authors.forename: Joanne
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D002412:Cations; D002462:Cell Membrane / Q000378:metabolism*; D016764:Cell Polarity / Q000235:genetics; D002831:Choroid Plexus / Q000166:cytology / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D033705:Equilibrative Nucleoside Transport Proteins / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018390:Gene Targeting; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D002412:Cations; D033705:Equilibrative Nucleoside Transport Proteins; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; C495988:SLC29A4 protein, human; D050493:Vesicular Monoamine Transport Proteins