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The Journal of Neuroscience, January 5, 2005, 25(1):239-246; doi:10.1523/JNEUROSCI.3699-04.2005

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Cellular/Molecular
NMDA Receptor Activation Mediates Copper Homeostasis in Hippocampal Neurons

Michelle L. Schlief,¹ Ann Marie Craig,² and Jonathan D. Gitlin¹

¹Edward Mallinckrodt Department of Pediatrics and ²Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110

Copper is an essential transition metal with a critical role in the CNS. This requirement is underscored by Menkes disease, a fatal neurodegenerative disorder of childhood resulting from the absence or dysfunction of a copper-transporting P-type ATPase. To elucidate the cell biological mechanisms of copper homeostasis in the CNS, a polyclonal antisera against Menkes ATPase was used in immunoblot and immunohistochemical studies, demonstrating abundant expression of this copper transporter in hippocampal neurons. Consistent with this observation, immunofluorescent analysis revealed Menkes ATPase in the late Golgi of hippocampal neurons in primary culture. Glutamate receptor activation was found to result in the rapid and reversible trafficking of Menkes ATPase to neuronal processes, independent of the intracellular copper concentration and specific for activation of the NMDA- but not AMPA/kainate-type glutamate receptors. Metabolic studies revealed that trafficking of Menkes ATPase after NMDA receptor activation is associated with rapid release of copper from hippocampal neurons. Menkes ATPase is directly required for this copper efflux, because similar studies in hippocampal neurons derived from mice lacking a functional Menkes ATPase demonstrated no copper release. Together, these data reveal a critical role for Menkes ATPase in the availability of an NMDA receptor-dependent, releasable pool of copper in hippocampal neurons and demonstrate a unique mechanism linking copper homeostasis and neuronal activation within the CNS.

Key words: Menkes disease; neurodegeneration; copper; hippocampal neurons; P-type ATPase; NMDA receptor

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Received Sep 7, 2004; revised November 16, 2004; accepted November 17, 2004.

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