D-aspartate regulates melanocortin formation and function: behavioral alterations in D-aspartate oxidase-deficient mice.
D-aspartate, an abundant D-amino acid enriched in neuroendocrine tissues, can be degraded by D-aspartate oxidase (Ddo). To elucidate the function of D-aspartate, we generated mice with targeted deletion of Ddo (Ddo(-/-)) and observe massive but selective augmentations of D-aspartate in various tissues. The pituitary intermediate lobe, normally devoid of D-aspartate from endogenous Ddo expression, manifests pronounced increases of immunoreactive D-aspartate in Ddo(-/-) mice. Ddo(-/-) mice show markedly diminished synthesis and levels of pituitary proopiomelanocortin/alpha-MSH, associated with decreased melanocortin-dependent behaviors. Therefore, Ddo is the endogenous enzyme that degrades D-aspartate, and Ddo-enriched organs, low in D-aspartate, may represent areas of high turnover where D-aspartate may be physiologically important.
Huang
Alex S
AS
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Beigneux
Anne
A
Weil
Zachary M
ZM
Kim
Paul M
PM
Molliver
Mark E
ME
Blackshaw
Seth
S
Nelson
Randy J
RJ
Young
Stephen G
SG
Snyder
Solomon H
SH
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015152:Blotting, Northern / Q000379:methods; D015992:Body Mass Index; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D050804:D-Aspartate Oxidase / Q000172:deficiency*; D026603:D-Aspartic Acid / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism; D011090:Polyenes / Q000378:metabolism*; D013739:Testosterone / Q000097:blood; D000521:alpha-MSH / Q000378:metabolism
D011090:Polyenes; C436145:melanocrocin; D013739:Testosterone; D010649:Phenylalanine; D026603:D-Aspartic Acid; D000521:alpha-MSH; D050804:D-Aspartate Oxidase