Mouse Hemokinin-1 Decapeptide Subjected to a Brain-specific Post-translational Modification

Abstract

Abstract. Background Tachykinins as a vast family of highly conserved peptides share the signature C-terminal motif FXGLM-NH2 (where X in mammals is F, Y, V; in fish, H, I, and in ascidians T) (1-3). The tachykinin mouse hemokinin-1 (mHK-1) discovered as an autocrine factor during pro-B lymphocyte differentiation introduced the group of endokinins (4) which also comprises human HK-1 (5), and its extended forms endokinin A (EKA) and endokinin (EKB) (6) or truncated forms such as the tachykinin human hemokinin (hHK-1) (4-11) (7). Tachykinins act as agonists on the three mammalian tachykinin receptors neurokinin 1, 2, 3 (NK1, NK2, NK3) with different potencies (5, 8). The hydrophobic C-terminal tachykinin motif activates the receptor, and the C-terminal amidation is crucial for activation (9, 10). Binding studies on the NK1 receptor showed mHK-1 as having similar binding affinity on this receptor as substance P (SP) (11-13) and a similar affinity for each of the mouse, rat and human NK1 receptors (5,7,14).The opposite effects of mHK-1 and SP in thermal hyperalgesia, have suggested that the two peptides could bind to different subtypes of the NK1 receptor (15, 16). The activation of NK1 receptor is related to the release of endogenous proopiomelanocortin, as well as the increased expression levels of the μ-opioid receptor in analgesia (17). Moreover, it was reported that the N-and C-terminal fragments of the mHK-1 elicited opposite biological effects (i.e. inhibition or induction of pruritus) when administered in rats, through the activation of the NK1 receptor (18). Recent evidence showed anxiolytic and anti-depressant-like actions for mHK-1 (19). The nociceptive behaviors induced by mHK-1 were inhibited by NMDA receptor antagonists. A significant increase in glutamate levels was observed, which was reduced by co-administration with NMDA receptor antagonists, suggesting that mHK-1-induced nociceptive effects may be mediated by the NMDA receptor (20). The Tachykinin receptor-1 (TACR1) gene was found among the neurotoxicityassociated genes in brain tissue that were significantly modulated after irradiation, suggesting that catenin-β1 and tumor suppressor-related transcription regulation are significantly activated by radiation and/or minocycline, suggesting minocycline as a potential neuroprotectant against radiation-induced damage (21). Moreover, the TACR3 was shown to be highly expressed in oral squamous cell carcinoma suggesting TAC3 was released by the peripheral sensory nerves which may act in tumor cells and that TACR3 signaling may, in turn, contribute to tumor progression (22).