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Copper Efflux from Murine Microvascular Cells Requires Expression of the Menkes Disease Cu-ATPase

Manuscript received 30 October 1997. Initial reviews completed 2 February 1998. Revision accepted 3 April 1998.

Yongchang Qian*, Evelyn Tiffany-Castiglionidagger , Jane Welshdagger , and Edward D. Harris*, **,

Departments of * Biochemistry & Biophysics, dagger  Veterinary Anatomy and Public Health and the ** Faculty of Nutrition, Texas A&M University, College Station, TX 77843 

Previously, we showed that the transport of Cu by PC12 pheochromocytoma cells and C6 glioma cells correlated with the expression of a Cu-transporting ATPase (Atp7a) that has been linked to Menkes disease. Here, we show that cerebrovascular endothelial (CVE) cells that comprise the blood-brain barrier (BBB) also express the gene for the Cu-ATPase. By using reverse transcription-polymerase chain reaction (RT-PCR) and primers designed from mouse Atp7a cDNA, we amplified a 925-bp and a 760-bp cDNA fragment from two extreme regions of Atp7a mRNA from murine CVE cells; 777 bp of the 925-bp fragment and 677 bp of the 760-bp fragment had a 99.7 and 100% sequence homology, respectively, with mouse Atp7a cDNA. The 777-bp sequences covered the heavy metal binding (Hmb) domain and the 677-bp fragment coded for residues at the -COOH terminus of Atp7a. A functional analysis showed that Cu efflux was blocked by the sulfhydryl reagent p-chloromercuribenzoate (p-CMB), a potential inhibitor of Atp7a function. This study provides strong evidence that a Cu-ATPase in the BBB controls the penetration of Cu into the brain and that lesions to the Cu-ATPase in CVE cells are a primary cause of low brain Cu levels in Menkes disease.

Key words: Cu transport, brain Cu, Menkes Cu-ATPase, cerebrovascular endothelial cells bullet  blood-brain barrier.

The Journal of Nutrition Vol. 128 No. 8 August 1998, pp. 1276-1282
Copyright ©1998 by the American Society for Nutritional Sciences




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