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Identification of an imidazoline binding protein: Creatine kinase and an imidazoline-2 binding site


Reference:

Kimura, A., Tyacke, R. J., Robinson, J. J., Husbands, S. M., Minchin, M. C. W., Nutt, D. J. and Hudson, A. L., 2009. Identification of an imidazoline binding protein: Creatine kinase and an imidazoline-2 binding site. Brain Research, 1279, pp. 21-28.

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Official URL:

http://dx.doi.org/10.1016/j.brainres.2009.04.044

Abstract

Drugs that bind to imidazoline binding proteins have major physiological actions. To date, three subtypes of such proteins, I-1, I-2 and I-3, have been proposed, although characterisations of these binding proteins are lacking. I-2 binding sites are found throughout the brain, particularly dense in the arcuate nucleus of the hypothalamus. Selective I-2 ligands demonstrate antidepressant-like activity and the identity of the proteins that respond to such ligands remained unknown until now. Here we report the isolation of a similar to 45 kDa imidazoline binding protein from rabbit and rat brain using a high affinity ligand for the I-2 subtype, 2-BFI, to generate an affinity column. Following protein sequencing of the isolated similar to 45 kDa imidazoline binding protein, we identified it to be brain creatine kinase (B-CK). B-CK shows high binding capacity to selective I-2 ligands; [H-3]-2-BFI (5 nM) specifically bound to B-CK (2330 +/- 815 fmol mg protein(-1)). We predicted an I-2 binding pocket near the active site of B-CK using molecular modelling. Furthermore, B-CK activity was inhibited by a selective I-2 irreversible ligand, where 20 mu M BU99006 reduced the enzyme activity by 16%, confirming the interaction between B-CK and the I-2 ligand. In summary, we have identified B-CK to be the similar to 45 kDa imidazoline binding protein and we have demonstrated the existence of an I-2 binding site within this enzyme. The importance of B-CK in regulating neuronal activity and neurotransmitter release may well explain the various actions of I-2 ligands in brain and the alterations in densities of I-2 binding sites in psychiatric disorders.

Details

Item Type Articles
CreatorsKimura, A., Tyacke, R. J., Robinson, J. J., Husbands, S. M., Minchin, M. C. W., Nutt, D. J. and Hudson, A. L.
DOI10.1016/j.brainres.2009.04.044
Uncontrolled Keywordsimidazoline binding protein, harmane and psychiatric disorders, creatine kinase, 2-bfi
DepartmentsFaculty of Science > Pharmacy & Pharmacology
RefereedYes
StatusPublished
ID Code14976

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