CAT2 arginine transporter deficiency significantly reduces iNOS-mediated NO production in astrocytes.
We have previously demonstrated that genetic ablation of cationic amino acid transporter 2 (Cat2) significantly inhibits nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) in activated macrophages. Here we report that iNOS activity is impaired by 84% in activated Cat2-deficient astrocytes. Cat2 ablation appears to reduce astrocyte NO synthesis by decreasing the uptake of the sole precursor, arginine, as well as by reducing the expression of iNOS following activation. Excessive or dysregulated NO production by activated astrocytes and other CNS cell types has been implicated in the pathogenesis of neurological disorders. Our results support the idea that manipulation of CAT2 transporter function might be useful for the therapeutic modulation of iNOS activity.
Manner
Cathyryne K
CK
Biomedical Sciences Graduate Program, Cancer Center and Department of Medicine, University of California San Diego, La Jolla, California 92093, USA. cmanner@uscd.edu
Nicholson
Benjamin
B
MacLeod
Carol L
CL
D027182:Amino Acid Transport System y+ / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000493:pharmacokinetics; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D027202:Cationic Amino Acid Transporter 2 / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism
D027182:Amino Acid Transport System y+; D027202:Cationic Amino Acid Transporter 2; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse