More than 100 peptides function throughout the central nervous system (CNS) as intercellular signaling molecules. Genetic manipulation/deletion of specific peptides in mice has connected peptides to various physiological functions, such as anxiety, seizure sensitivity, pair bonding and obesity (11;14;22;23). One posttranslational modification, ?-amidation, is necessary to confer biological activity to more than half of the neuropeptides and peptide hormones (15; 16). Amidation only occurs through the enzymatic reaction catalyzed by peptidylglycine ?-amidating monooxgenase (PAM) (12). Genetic deletion of PAM results in embryonic lethality (12). The reaction catalyzed by PAM cannot occur without adequate levels of copper and ascorbic acid (vitamin C). Humans must obtain both copper and ascorbic acid from their diets. Thus, the goal of this proposal is to use mice heterozygous for PAM (PAM) to identify the physiological systems that are most sensitive to limited peptidergic amidation. Deficits identified in PAM mice will identify the physiological processes most likely to be affected by mutations in PAM or by the effects of dietary deficiencies in copper or vitamin C on peptidergic amidation. Viral replacement of PAM, pharmacological supplementation/depletion of copper, and delivery of specific peptides will be used to rescue or exacerbate the physiological deficits identified. Knowing the physiological processes and behaviors most sensitive to lack of peptidergic amidation in the PAM mouse model, it will then be possible to extend these observations to humans. A role for limited amidation due to a genetic deficiency in PAM or dietary deficiencies in copper and ascorbate in anxiety disorders, seizure disorders and neuroendocrine disorders can then be assessed in humans ? ? ?
| Bousquet-Moore, Danielle; Mains, Richard E; Eipper, Betty A (2010) Peptidylgycine ?-amidating monooxygenase and copper: a gene-nutrient interaction critical to nervous system function. J Neurosci Res 88:2535-45 |
| Bousquet-Moore, D; Ma, X M; Nillni, E A et al. (2009) Reversal of physiological deficits caused by diminished levels of peptidylglycine alpha-amidating monooxygenase by dietary copper. Endocrinology 150:1739-47 |
