Simon Lemaire, Ph.D.
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Professor Faculty of Medicine 451 Smyth Road Ottawa, ON K1H 8M5 Tel.: (613) 562-5800 (8350) FAX: (613) 562-5434 Email: slemaire@uottawa.ca |
Structure and function of C-terminal histone H4 peptides.
Structure and function of C-terminal histone H4 peptides. The research interest of our laboratory has recently been focussed on the isolation, structural identification, synthesis and determination of the biological activity of histogranin (HN). HN is a slightly modified C-terminal histone H4 peptide present in various rat tissues including the spleen, lungs, bone marrow and brain. It was first coined for its in vivo modulation of N-methyl-D-aspartate (NMDA)-induced convulsions in mice. Recently, HN and related peptides were found to display non-opioid analgesic activities in various animal models of pain. The design and synthesis of small molecules (cyclic tetrapeptides and non-peptides) on the basis of the structure of HN were among our first priorities in order to determine the structure requirement and mode of action of HN for its antinociceptive effects. The mechanism by which HN and related compounds alleviate pain is still unknown, but a close correlation was made between the abilities of HN and related peptides to produce analgesia in the mouse writhing test and compete with the binding of an HN-like radiolabelled peptide to rat alveolar macrophages membranes. Stimulation of the HN receptor on isolated rat alveolar macrophages inhibited forskolin stimulation of cAMP levels as well as the induction of COX-2 and synthesis of PGE2, a pain factor. Our hypothesis is that HN and related peptides bind to a specific HN receptor on central and/or peripheral macrophages and inhibit the synthesis of factors involved in the production of pain. The elucidation of the nature of the HN receptor on macrophages is an important research issue in our laboratorary.
Some Selected References
Shukla, V.K., Lemaire, S., Ibrahim, I.H., Cyr, T.D., Chen, Y. and Michelot, M. (1993) Design of potent and selective dynorphin A-related peptides devoid of supraspinal motor effects in mice. Can. J. Physiol. Pharmacol.71:211-216.
Lemaire, S., Shukla, V.K., Rogers, C., Ibrahim, I.H., L apierre, C., Parent, P. and Dumont, M. (1993) Isolation and characterization of histogranin, a natural peptide with N-methyl-D-aspartate antagonist activity. Eur. J. Pharmacol. Molec. Pharmacol. Sec. 245:247-256.
Dumont, M. and Lemaire, S. (1993) Characterization of non-opioid [3H]dynorphin A-(1-13) binding sites in the rat heart. J. Mol. Cell. Cardiol. 25:983-991.