Hemokinin 1 (human)

Human hemokinin-1 promotes migration of melanoma cells and increases MMP-2 and MT1-MMP expression by activating tumor cell NK1 receptors.[Pubmed:27458061]

Peptides. 2016 Sep;83:8-15.

Receptors and their regulatory peptides are aberrantly expressed in tumors, suggesting a potential tumor therapy target. Human hemokinin-1 (hHK-1) is a tachykinin peptide ligand of the neurokinin-1 (NK1) receptor which is overexpressed in melanoma and other tumor tissues. Here, we investigated the role of hHK-1 and the NK1 receptor in melanoma cell migration. NK1 receptor expression was associated with melanoma metastatic potential. Treatment with hHK-1 significantly enhanced A375 and B16F10 melanoma cell migration and an NK1 receptor antagonist L732138 blocked this effect. MMP-2 and MT1-MMP expression were up-regulated in hHK-1-treated melanoma cells and cell signaling data suggested that hHK-1 induced phosphorylation of ERK1/2, JNK and p38 by way of PKC or PKA. Kinase activation led to increased MMP-2 and MT1-MMP expression and melanoma cell migration induced by hHK-1. Thus, hHK-1 and the NK1 receptor are critical to melanoma cell migration and each may be a promising chemotherapeutic target.

Membrane-induced structure of novel human tachykinin hemokinin-1 (hHK1).[Pubmed:26297926]

Biopolymers. 2015 Dec;103(12):702-10.

PPT-C encoded hemokinin-1(hHK-1) of Homo sapiens (TGKASQFFGLM) is a structurally distinct neuropeptide among the tachykinin family that participate in the NK-1 receptor downstream signaling processes. Subsequently, signal transduction leads to execution of various effector functions which includes aging, immunological, and central nervous system (CNS) regulatory actions. However the conformational pattern of ligand receptor binding is unclear. The three-dimensional structure of the hemokinin-1 in aqueous and micellar environment has been studied by one and two-dimensional proton nuclear magnetic resonance (2D 1H-NMR spectroscopy) and distance geometry calculations. Data shows that hemokinin-1 was unstructured in aqueous environment; anionic detergent SDS induces alpha-helix formation. Proton NMR assignments have been carried out with the aid of correlation spectroscopy (gradient-COSY and TOCSY) and nuclear Overhauser effect spectroscopy (NOESY and ROESY) experiments. The inter proton distances and dihedral angle constraints obtained from the NMR data have been used in torsion angle dynamics algorithm for NMR applications (CYANA) to generate a family of structures, which have been refined using restrained energy minimization and dynamics. Helical conformation is observed from residue K3-M11. The conformational range of the peptide revealed by NMR studies has been analyzed in terms of characteristic secondary features. Observed conformational features have been compared to that of Substance P potent NK1 agonist. Thus the report provides a structural insight to study hHK-1-NK1 interaction that is essential for hHK1 based signaling events.

[Particularities of Spatial Organization of Human Hemokinin-1 and Mouse/Rat Hemokinin-1 Molecules].[Pubmed:26349209]

Biofizika. 2015 May-Jun;60(3):457-70.

By molecular mechanics method the conformational properties of two molecules of the tachykinin family, human hemokinin-1 and mouse/rat hemokinin-1, each consisting of 11 amino acids, have been investigated. On the basis of a step-by-step approach we determined the energetically favorable spatial structures of these molecules and their fragments represented as a set of conformations characterized by the relatively labile N-terminal tripeptide and conformationally rigid C-terminal segment. It was shown that conformationally conservative C-terminal octapeptide of the molecules preferably forms two conformations with different structural types of the peptide chain. One of these conformations has an alpha-helical structure, and the other forms the chain's turn that led to an alpha helical turn at the C-terminus. As a result of calculations the energetically favorable ranges of the values of the dihedral angles and orientations of all the residues in low energy conformational states of the molecules were shown. Due to conformational analysis of separate fragments it was possible to trace the process of the second structure formation in these molecules. Based on the results obtained the contribution of inter-residues interaction energy was determined and the role of the each residue in the formation of the optimal spatial structures of hemokinin-1 molecules was estimated.

Hemokinin-1 stimulates prostaglandin E(2) production in human colon through activation of cyclooxygenase-2 and inhibition of 15-hydroxyprostaglandin dehydrogenase.[Pubmed:21957267]

J Pharmacol Exp Ther. 2012 Jan;340(1):27-36.

Hemokinin-1 (HK-1) is a newly identified tachykinin, originating from the immune system rather than neurons, and may participate in the immune and inflammatory response. In colonic mucosa of patients with inflammatory bowel disease (IBD), up-regulation of the TAC4 gene encoding HK-1 and increased production of prostaglandin E(2) (PGE(2)) occur. Our aim was to examine the mechanistic link between human HK-1 and PGE(2) production in normal human colon. Exogenous HK-1 (0.1 muM) for 4 h evoked an increased PGE(2) release from colonic mucosal and muscle explants by 10- and 3.5-fold, respectively, compared with unstimulated time controls. The HK-1-stimulated PGE(2) release was inhibited by the tachykinin receptor antagonists (S)1-2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl-4 -phenyl-l azonia-bicyclo[2.2.2]octane (SR140333) [neurokinin-1 (NK(1))] and N-[(2S)-4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-met hylbenzamide (SR48968) [neurokinin-2 (NK(2))] and was also inhibited by the cyclooxygenase (COX)-2 inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide) (NS-398) but not by the COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560). A parallel study with substance P showed similar results. Molecular studies with HK-1-treated explants demonstrated a stimulatory effect on COX-2 expression at both transcription and protein levels. It is noteworthy that this was coupled with HK-1-induced down-regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA and protein expression. Immunoreactivity for 15-PGDH occurred on inflammatory cells, epithelial cells, platelets, and ganglia. This finding provides an additional mechanism for HK-1-evoked PGE(2) increase, in which HK-1 may interfere with the downstream metabolism of PGE(2) by suppressing 15-PGDH expression. In conclusion, our results uncover a novel inflammatory role for HK-1, which signals via NK(1) and NK(2) receptors to regulate PGE(2) release from human colonic tissue, and may further explain a pathological role for HK-1 in IBD when abnormal levels of PGE(2) occur.

Pharmacological profile of the novel mammalian tachykinin, hemokinin 1.[Pubmed:11786503]

Br J Pharmacol. 2002 Jan;135(1):266-74.

1. The effects of the novel mammalian tachykinin, hemokinin 1 (HEK-1), have been investigated by radioligand binding and functional in vitro and in vivo experiments. 2. Similar to SP (K(i)=0.13 nM), HEK-1 inhibited in a concentration-dependent manner and with high affinity [(3)H]-substance P (SP) binding to human NK(1) receptor (K(i)=0.175 nM) while its affinity for [(125)I]-neurokinin A (NKA) binding at human NK(2) receptor was markedly lower (K(i)=560 nM). 3. In isolated bioassays HEK-1 was a full agonist at tachykinin NK(1), NK(2) and NK(3) receptors. In the rat urinary bladder (RUB) HEK-1 was about 3 fold less potent than SP. In the rabbit pulmonary artery (RPA) HEK-1 and in the guinea-pig ileum (GPI), HEK-1 was about 500 fold less potent than NKA and NKB, respectively. 4. The responses to HEK-1 were antagonized by GR 82334 in RUB (pK(B)=5.6+/-0.07), by nepadutant in RPA (pK(B)=8.6+/-0.04) and by SR 142801 in GPI (pK(B)=9.0+/-0.2) with apparent affinities comparable to that measured against tachykinin NK(1), NK(2) and NK(3) receptor-selective agonists, respectively. 5. Intravenous HEK-1 produced dose-related decrease of blood pressure in anaesthetized guinea-pigs (ED(50)=0.1 nmol kg(-1)) and salivary secretion in anaesthetized rats (ED(50)=6 nmol kg(-1)) with potencies similar to that of SP. All these effects were blocked by the selective tachykinin NK(1) receptor antagonist, SR 140333. 6. We conclude that HEK-1 is a full agonist at tachykinin NK(1), NK(2) and NK(3) receptors, possesses a remarkable selectivity for NK(1) as compared to NK(2) or NK(3) receptors and acts in vivo experiments with potency similar to that of SP.

Identification, localization and receptor characterization of novel mammalian substance P-like peptides.[Pubmed:12383518]

Gene. 2002 Aug 21;296(1-2):205-12.

Hemokinin-1 (HK-1) is a novel substance P (SP)-like peptide that is encoded by the preprotachykinin C (PPT-C) gene recently identified in mouse B cells and shown to be a potentially important regulator of B cell development (Nat. Immunol. 1 (2000) 392). We have now isolated and characterized the human and rat orthologs of PPT-C and examined activities of human and mouse HK-1 on the three tachykinin receptors, neurokinin-1-3 (NK1-3). The rat PPT-C polypeptide is highly homologous to mouse PPT-C and contains the same processing sites to generate predicted HK-1. The human PPT-C polypeptide is also homologous to mouse PPT-C, however, it contains two potential monobasic cleavage sites rather than a single dibasic cleavage site at the amino-terminal end of the predicted HK-1 peptide. Thus, human PPT-C has the potential to generate full length predicted HK-1 as well as a truncated version (HK-1(4-11)). Polymerase chain reaction analysis revealed that both human and mouse PPT-C were expressed in a variety of tissues with strong signals detected in the skin of both species and in the mouse brain. Binding and functional analysis indicated that human and mouse HK-1 peptides were nearly identical to SP in their overall activity profile on the three NK receptors with the most potent affinity for the NK1 receptor. The results indicate that PPT-C encodes another high affinity ligand of the NK1 receptor which may play an important role in mediating some of the physiological roles previously assigned to the NK1 receptor.