title: Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels.
abstract: Human Cayman ataxia and mouse or rat dystonia are linked to mutations in the genes ATCAY (Atcay) that encode BNIP-H or Caytaxin, a brain-specific member of the BNIP-2 family. To explore its possible role(s) in neuronal function, we used protein precipitation and matrix-assisted laser desorption/ionisation mass spectrometry and identified kidney-type glutaminase (KGA) as a novel partner of BNIP-H. KGA converts glutamine to glutamate, which could serve as an important source of neurotransmitter. Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly. Immunohistochemistry and in situ hybridisation revealed high BNIP-H expression in hippocampus and cerebellum, broadly overlapping with the expression pattern previously reported for KGA. Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity. These results strongly suggest that through binding to KGA, BNIP-H could regulate glutamate synthesis at synapses during neurotransmission. Thus, loss of BNIP-H function could render glutamate excitotoxicity or/and deregulated glutamatergic activation, leading to ataxia, dystonia or other neurological disorders.
authors.affiliation: Department of Biological Sciences, 14 Science Drive 4, Faculty of Science, National University of Singapore, Singapore 117543, Republic of Singapore.
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Buschdorf
authors.forename: Li
authors.initials: L
authors.lastname: Li Chew
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Cao
authors.forename: Feng-Yi
authors.initials: FY
authors.lastname: Liang
authors.forename: Yih-Cherng
authors.initials: YC
authors.lastname: Liou
authors.forename: Yi Ting
authors.initials: YT
authors.lastname: Zhou
authors.forename: Boon Chuan
authors.initials: BC
authors.lastname: Low
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000166:cytology; D018236:Carcinoma, Embryonal / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D005971:Glutamates / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016501:Neurites / Q000201:enzymology*; D011817:Rabbits; D051381:Rats
chemical_list: D005971:Glutamates; D009419:Nerve Tissue Proteins; C508764:atcay protein, rat; D005972:Glutaminase