Hemokinins、血紅素肽的介紹

Definition

Hemokinin-1 (HK-1) is a novel substance P (SP)-like peptide that is encoded by the preprotachykinin C (PPT-C) gene. 

Structural Characteristics

HK-1 shares the common C-terminal sequence Phe-X-Gly-Leu-MetNH2 typical of the tachykinin peptide family - SP, Neurokinin A (NKA) and Neurokinin B (NKB). The residue in position X of SP and HK-1 sequence is aromatic (Phe and Tyr, respectively) whereas a Val residue is present in the corresponding sequence of NKA/NKB. On the other hand the N-terminal sequence of mammalian tachykinins is highly divergent HK-1 and SP share a positively-charged Arg residue in position 11 and a Gln residue in position 6, but diverging residues at all other positions of the N-terminal sequence. No other match exists in the N terminal region of HK-1 and natural tachykinins with the only exception of Thr in position 8 which is shared by NKA (SP bears a Pro residue in this position)1. 

Mode of action

A study provides evidence that HK-1 is full agonist at the three known tachykinin receptors: NK1 receptor, NK2 receptor and NK3 receptor, as compared to the natural tachykinins SP, NKA or NKB, respectively. Receptor selective antagonists (GR 82334, nepadutant and SR 142801) were used to verify the assumption that the responses to HK-1 were indeed ascribable to stimulation of tachykinin receptors. Further the results indicated that HK-1 is almost equipotent to SP in activating NK1 receptors whereas it is about 500 fold less potent than NKA or NKB in activating NK2 and NK3 receptors, respectively. In other words, HK-1 has preferential affinity for NK1 over NK2/NK3 receptors1.

Functions

Hemokinin regulates B lymphopoiesis - Hemokinin -1 has several biological activities that are similar to the most studied tachykinin, substance P. However, HK-1 also has properties that are indicative of a critical role in mouse B cell development. Further it has been shown that HK-1 stimulated the proliferation of interleukin 7-expanded B cell precursors, whereas substance P had no effect. HK-1, but not substance P, promoted the survival of freshly isolated bone marrow B lineage cells or cultured, lipopolysaccharide-stimulated pre-B cells. N-acetyl-l-trytophan-3,5-bistrifluromethyl benzyl ester, a tachykinin receptor antagonist, increased apoptosis of these cells and in vivo administration of this antagonist led to specific reductions of the pre-B cell population in the bone marrow and the newly generated B cell population in the spleen. Thus, HK-1 may be an autocrine factor that is important for the survival of B cell precursors at a critical phase of development2. 

Human hemokinin-1 and human hemokinin-1(4–11): suppress proliferation and induce differentiation in human promyelocyte leukemia cell line, HL-60 - Human hemokinin-1 (h HK-1) and its truncated form h HK-1(4–11) are mammalian tachykinin peptides encoded by the TAC4 gene in human. The tachykinins have shown immuno-regulatory activities in humans. A study show that h HK-1 displayed inhibitory effects on the proliferation of HL-60 cells in a dose- and time-dependent manner. The effect of suppressing proliferation induced by these peptides was accompanied by an accumulation of cell cycle in the S phase. The effects induced by h HK-1(4–11) on HL-60 cells were similar to that of h HK-1, indicating that it is the active fragment of h HK-1. However these effects induced by h HK-1 or h HK-1(4–11) were not antagonized by the NK1 receptor antagonist SR140333 or the NK2 receptor antagonist SR48968. Further the results indicated that h HK-1 and h HK-1(4–11) were able to significantly inhibit proliferation and induce differentiation and S phase arrest of a human promyelocyte leukemia cell line HL-60, which may not be mediated through the activation of classical tachykinin NK1 receptors and tachykinin NK2 receptors3.

Hemokinin-1 induced relaxing response in porcine coronary arteries - Rat and mouse hemokinin-1(r/m hemokinin-1) is a recently described member of the tachykinin family. The r/m Hemokinin-1 evoked a marked endothelium-dependent vasodilatation of coronary arteries mediated by activation of endothelial tachykinin NK(1) receptors. Two components contributed to this r/m hemokinin-1-elicited vasodilatation, the first of which was endothelium-derived hyperpolarizing factor (EDHF), which played a major role. This EDHF was identified as a potassium current through certain kinds of potassium channels on the endothelial cell membrane of porcine coronary arteries. Specific antagonists of Ca(2+)-activated K(+) channels (dequalinium and clotrimazole) did not have an inhibitory effect on the r/m hemokinin-1-induced vasodilatation, whereas they did on the substance P-induced vasodilatation. When potassium ion efflux was impaired by a high K(+) concentration (30 mM) or removal of K(+) from the surroundings, NO synthesis was triggered by r/m hemokinin-1 to produce an equivalent EDHF (K(+))-independent vasorelaxation4.

 Reference:

1. Francesca Bellucci, Francesca Carini, Claudio Catalani, Paola Cucchi, Alessandro Lecci, Stefania Meini, Riccardo Patacchini, Laura Quartara, Renzo Ricci, Manuela Tramontana, Sandro Giuliani, and Carlo Alberto Maggi (2002). Pharmacological profile of the novel mammalian tachykinin, hemokinin 1. Br. J. Pharmacol., 135(1), 266–274.

2. Zhang Y, Lu L, Furlonger C, Wu G E, Palge C P (2000). Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nature Immunol., 1, 392–397.

3. You Li Zhao, Yan Tao, Cai Yun Fu, Zi Qing Kong, Qiang Chen and Rui Wang (2002). Human hemokinin-1 and human hemokinin-1(4–11), mammalian tachykinin peptides, suppress proliferation and induce differentiation in HL-60 cells. Gene., 296 (1-2), 205-212.

4. Long Y, Fu CY, Tian XZ, Chen J, Han M, Wang R (2007). Eur. J. Pharmacol., 569(1-2), 119-125.