Interactions of peptide amidation and copper: novel biomarkers and mechanisms of neural dysfunction.
Mammalian genomes encode only a small number of cuproenzymes. The many genes involved in coordinating copper uptake, distribution, storage and efflux make gene/nutrient interactions especially important for these cuproenzymes. Copper deficiency and copper excess both disrupt neural function. Using mice heterozygous for peptidylglycine alpha-amidating monooxygenase (PAM), a cuproenzyme essential for the synthesis of many neuropeptides, we identified alterations in anxiety-like behavior, thermoregulation and seizure sensitivity. Dietary copper supplementation reversed a subset of these deficits. Wildtype mice maintained on a marginally copper-deficient diet exhibited some of the same deficits observed in PAM(+/-) mice and displayed alterations in PAM metabolism. Altered copper homeostasis in PAM(+/-) mice suggested a role for PAM in the cell type specific regulation of copper metabolism. Physiological functions sensitive to genetic limitations of PAM that are reversed by supplemental copper and mimicked by copper deficiency may serve as indicators of marginal copper deficiency.
Bousquet-Moore
Danielle
D
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030-3401, USA.
Prohaska
Joseph R
JR
Nillni
Eduardo A
EA
Czyzyk
Traci
T
Wetsel
William C
WC
Mains
Richard E
RE
Eipper
Betty A
BA
D000818:Animals; D001008:Anxiety Disorders / Q000178:diet therapy / Q000378:metabolism*; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology*; D003300:Copper / Q000172:deficiency / Q000378:metabolism* / Q000627:therapeutic use; D004032:Diet; D019587:Dietary Supplements; D005260:Female; D006579:Heterozygote; D006706:Homeostasis / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D006899:Mixed Function Oxygenases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010433:Pentylenetetrazole; D010455:Peptides / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology
D009097:Multienzyme Complexes; D010455:Peptides; D003300:Copper; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D010433:Pentylenetetrazole