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Peptidylglycine α-amidating monooxygenase heterozygosity alters brain copper handling with region specificity.

Publication ,  Journal Article
Gaier, ED; Miller, MB; Ralle, M; Aryal, D; Wetsel, WC; Mains, RE; Eipper, BA
Published in: J Neurochem
December 2013

Copper (Cu), an essential trace element present throughout the mammalian nervous system, is crucial for normal synaptic function. Neuronal handling of Cu is poorly understood. We studied the localization and expression of Atp7a, the major intracellular Cu transporter in the brain, and its relation to peptidylglycine α-amidating monooxygenase (PAM), an essential cuproenzyme and regulator of Cu homeostasis in neuroendocrine cells. Based on biochemical fractionation and immunostaining of dissociated neurons, Atp7a was enriched in post-synaptic vesicular fractions. Cu followed a similar pattern, with ~ 20% of total Cu in synaptosomes. A mouse model heterozygous for the Pam gene (PAM+/−) was selectively Cu deficient in the amygdala. As in cortex and hippocampus, Atp7a and PAM expression overlap in the amygdala, with highest expression in interneurons. Messenger RNA levels of Atox-1 and Atp7a, which deliver Cu to the secretory pathway, were reduced in the amygdala but not in the hippocampus in PAM+/− mice, GABAB receptor mRNA levels were similarly affected. Consistent with Cu deficiency, dopamine β-monooxygenase function was impaired as evidenced by elevated dopamine metabolites in the amygdala, but not in the hippocampus, of PAM+/− mice. These alterations in Cu delivery to the secretory pathway in the PAM+/− amygdala may contribute to the physiological and behavioral deficits observed. Atp7a, a Cu-transporting P-type ATPase, is localized to the trans-Golgi network and to vesicles distributed throughout the dendritic arbor. Tissue-specific alterations in Atp7a expression were found in mice heterozygous for peptidylglycine α-amidating monooxygenase (PAM), an essential neuropeptide-synthesizing cuproenzyme. Atp7a and PAM are highly expressed in amygdalar interneurons. Reduced amygdalar expression of Atox-1 and Atp7a in PAM heterozygous mice may lead to reduced synaptic Cu levels, contributing to the behavioral and neurochemical alterations seen in these mice.

Duke Scholars

Published In

J Neurochem

DOI

EISSN

1471-4159

Publication Date

December 2013

Volume

127

Issue

5

Start / End Page

605 / 619

Location

England

Related Subject Headings

  • trans-Golgi Network
  • Subcellular Fractions
  • Pregnancy
  • Neurology & Neurosurgery
  • Multienzyme Complexes
  • Mixed Function Oxygenases
  • Mice, Mutant Strains
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

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Chicago
ICMJE
MLA
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Gaier, E. D., Miller, M. B., Ralle, M., Aryal, D., Wetsel, W. C., Mains, R. E., & Eipper, B. A. (2013). Peptidylglycine α-amidating monooxygenase heterozygosity alters brain copper handling with region specificity. J Neurochem, 127(5), 605–619. https://doi.org/10.1111/jnc.12438
Gaier, Eric D., Megan B. Miller, Martina Ralle, Dipendra Aryal, William C. Wetsel, Richard E. Mains, and Betty A. Eipper. “Peptidylglycine α-amidating monooxygenase heterozygosity alters brain copper handling with region specificity.J Neurochem 127, no. 5 (December 2013): 605–19. https://doi.org/10.1111/jnc.12438.
Gaier ED, Miller MB, Ralle M, Aryal D, Wetsel WC, Mains RE, et al. Peptidylglycine α-amidating monooxygenase heterozygosity alters brain copper handling with region specificity. J Neurochem. 2013 Dec;127(5):605–19.
Gaier, Eric D., et al. “Peptidylglycine α-amidating monooxygenase heterozygosity alters brain copper handling with region specificity.J Neurochem, vol. 127, no. 5, Dec. 2013, pp. 605–19. Pubmed, doi:10.1111/jnc.12438.
Gaier ED, Miller MB, Ralle M, Aryal D, Wetsel WC, Mains RE, Eipper BA. Peptidylglycine α-amidating monooxygenase heterozygosity alters brain copper handling with region specificity. J Neurochem. 2013 Dec;127(5):605–619.
Journal cover image

Published In

J Neurochem

DOI

EISSN

1471-4159

Publication Date

December 2013

Volume

127

Issue

5

Start / End Page

605 / 619

Location

England

Related Subject Headings

  • trans-Golgi Network
  • Subcellular Fractions
  • Pregnancy
  • Neurology & Neurosurgery
  • Multienzyme Complexes
  • Mixed Function Oxygenases
  • Mice, Mutant Strains
  • Mice, Inbred C57BL
  • Mice
  • Male