Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue
Ip, V and Liu, JJ and Mercer, JFB and McKeage, MJ, Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue, Molecular pain, 6, (53) pp. 1-10. ISSN 1744-8069 (2010) [Refereed Article]
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Background: ATP7A, ATP7B and CTR1 are metal transporting proteins that control the cellular disposition of
copper and platinum drugs, but their expression in dorsal root ganglion (DRG) tissue and their role in platinuminduced
neurotoxicity are unknown. To investigate the DRG expression of ATP7A, ATP7B and CTR1, lumbar DRG
and reference tissues were collected for real time quantitative PCR, RT-PCR, immunohistochemistry and Western
blot analysis from healthy control adult rats or from animals treated with intraperitoneal oxaliplatin (1.85 mg/kg) or
drug vehicle twice weekly for 8 weeks.
Results: In DRG tissue from healthy control animals, ATP7A mRNA was clearly detectable at levels similar to those
found in the brain and spinal cord, and intense ATP7A immunoreactivity was localised to the cytoplasm of cell
bodies of smaller DRG neurons without staining of satellite cells, nerve fibres or co-localisation with phosphorylated
heavy neurofilament subunit (pNF-H). High levels of CTR1 mRNA were detected in all tissues from healthy control
animals, and strong CTR1 immunoreactivity was associated with plasma membranes and vesicular cytoplasmic
structures of the cell bodies of larger-sized DRG neurons without co-localization with ATP7A. DRG neurons with
strong expression of ATP7A or CTR1 had distinct cell body size profiles with minimal overlap between them.
Oxaliplatin treatment did not alter the size profile of strongly ATP7A-immunoreactive neurons but significantly
reduced the size profile of strongly CTR1-immunoreactive neurons. ATP7B mRNA was barely detectable, and no
specific immunoreactivity for ATP7B was found, in DRG tissue from healthy control animals.
Conclusions: In conclusion, adult rat DRG tissue exhibits a specific pattern of expression of copper transporters
with distinct subsets of peripheral sensory neurons intensely expressing either ATP7A or CTR1, but not both or
ATP7B. The neuron subtype-specific and largely non-overlapping distribution of ATP7A and CTR1 within rat DRG
tissue may be required to support the potentially differing cuproenzyme requirements of distinct subsets of
sensory neurons, and could influence the transport and neurotoxicity of oxaliplatin.