Pharmacological profile of the novel mammalian tachykinin, hemokinin 1

Bellucci, Francesca; Carini, F; Catalani, Claudio; Cucchi, Paola; Lecci, Alessandro; Meini, Stefania; Patacchini, Riccardo; Quartara, Laura; Ricci, Renzo; Tramontana, Manuela; Giuliani, Sandro; Maggi, Carlo Alberto

doi:10.1038/sj.bjp.0704443

Cited by 103 publications

(65 citation statements)

References 31 publications

(45 reference statements)

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“…Diversity in the amino acid sequence between these naturally occurring NK 1 ligands appears moderately flexible, and this is especially significant with regard to their role and functions. In bioassays, mHK-1 produces hypotension in guinea pigs and salivary secretion in rats in the same way as SP (12). In rats, we have shown that the complex, but characteristic, regional hemodynamic response to SP (26) is closely mimicked by EKA͞B.…”

Section: Discussionmentioning

confidence: 72%

“…In mice and humans, the TAC4 gene is widely distributed with expression levels and sites distinct from that of the TAC1 gene, particularly within the peripheral tissues. The peripheral expression of TAC4 is therefore particularly intriguing because mHK-1 has been shown to be a full agonist at each of the three NK receptors, with a remarkable selectivity for the NK 1 receptor that is similar to that of SP (11,12). This leads us to propose that mHK-1 and EKA͞B are the peripheral SP-like endocrine͞paracrine agonists where SP is not expressed.…”

Section: Discussionmentioning

confidence: 99%

“…This tachykinin is uniquely expressed outside of neuronal tissue in immune tissues (11). It has subsequently been found to be a full agonist at the NK 1 , NK 2 , and NK 3 receptors, with highest selectivity for NK 1 (12,13). Here, we report the identification, pharmacology, and cardiovascular physiology of four previously uncharacterized members of the human tachykinin family encoded on the human TAC4 gene that we have named endokinins (EK) A-D. As their name suggests, they are mainly distributed in the periphery, and their presence in the placenta suggests that these tachykinins may be involved in controlling blood flow during pregnancy.…”

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confidence: 99%

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Characterization of the endokinins: Human tachykinins with cardiovascular activity

Page

Bell

Gardiner

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

143

161

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We report four human tachykinins, endokinins A, B, C, and D (EKA-D), encoded from a single tachykinin precursor 4 gene that generates four mRNAs (␣, ␤, ␥, and ␦). Tachykinin 4 gene expression was detected primarily in adrenal gland and in the placenta, where, like neurokinin B, significant amounts of EKB-like immunoreactivity were detected. EKA͞B 10-mers displayed equivalent affinity for the three tachykinin receptors as substance P (SP), whereas a 32-mer N-terminal extended form of EKB was significantly more potent than EKA͞B or SP. EKC͞D, which possess a previously uncharacterized tachykinin motif, FQGLL-NH2, displayed low potency. EKA͞B displayed identical hemodynamic effects to SP in rats, causing short-lived falls in mean arterial blood pressure associated with tachycardia, mesenteric vasoconstriction, and marked hindquarter vasodilatation. Thus, EKA͞B could be the endocrine͞paracrine agonists at peripheral SP receptors and there may be as yet an unidentified receptor(s) for EKC͞D.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Characterization of the endokinins: Human tachykinins with cardiovascular activity

Page

Bell

Gardiner

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

143

161

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“…Its primary ligand is SP, but other members of the tachykinin family can also activate NK-1R, including hemokinin-1 at equimolar affinity to SP (29,30), and neurokinins A and B at lower affinity (31). There are several potential sources of SP that could activate tr-NK-1R in CAC.…”

Section: Discussionmentioning

confidence: 99%

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Gillespie¹,

Leeman²,

Watts³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitisassociated cancer.colon cancer | receptor splice variants | substance P | IBD C hronic inflammation is associated with a higher rate of cancer development in various organs (1). More specifically, patients with ulcerative colitis (UC) are at high risk for developing colorectal cancer (2); both extent and duration of intestinal inflammation further increase risk (3, 4). These associations suggest that chronic intestinal inflammation is a causative factor in carcinogenesis in patients with UC, and that there is a causal link between chronic inflammation and increased risk of cancer. These observations raise the question of the signaling pathways by which long-standing inflammation might underlie the development of cancer.Substance P (SP) is a proinflammatory neuropeptide described by von Euler and Gaddum (5) and later isolated and characterized by Chang and Leeman (6). SP is synthesized by a variety of cells, most notably neurons and inflammatory cells such as macrophages (7). SP's primary receptor, the neurokinin-1 receptor (NK-1R), can mediate a variety of physiologic and pathophysiologic responses, including cell proliferation, migration, and inflammation (8). The NK-1R has been identified in epithelial cells in rodent models of colonic inflammation (9, 10) and in patients with UC as well as Crohn disease (11)(12)(13)(14). However, not all of these studies are in agreement regarding epithelial NK-1R e...

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“…Structurally, it most closely resembles SP in that both have multiple cationic residues at the N terminus and an aromatic amino acid occupying the variable X position of the tachykinin motif. Moreover, HK-1 demonstrates similar binding affinity and preference for the SP receptor, NK-1 (21)(22)(23)(24)(25)(26). However, there are remarkable differences in tissue distribution between HK-1 and SP.…”

mentioning

confidence: 97%

Hemokinin-1 Activates the MAPK Pathway and Enhances B Cell Proliferation and Antibody Production

Wang

Zhang

et al. 2010

The Journal of Immunology

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Hemokinin 1 (HK-1) is a substance P-like tachykinin peptide predominantly expressed in non-neuronal tissues. In addition to a prominent function in lymphoid development, recent studies indicate a potential role for HK-1 in immunoregulation. The current study was focused on its action on mature B cells. Despite the negligible effect on its own, HK-1 exhibited a profound influence on B cell activation elicited by several classical signals, including LPS stimulation, BCR cross-linking, and CD40 ligation. Cells therefore showed enhanced proliferation, survival, and CD80/86 expression, and produced more IgM with a higher frequency of Ab-forming cells. Biochemical analysis revealed that HK-1 alone was sufficient to induce the activation of MAPKs and the expression of Blimp-1 and Xbp-1 in B cells. Nevertheless, costimulation with a known B cell activator resulted in much enhanced phosphorylation of MAPKs and transcriptional activation of Blimp-1 and Xbp-1. Overall, these data support that HK-1 provides an important costimulatory signal for B cell activation, possibly through synergistic activation of the MAPK pathway and induction of transcription factors critical for plasmacytic differentiation.

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Pharmacological profile of the novel mammalian tachykinin, hemokinin 1

Cited by 103 publications

References 31 publications

Characterization of the endokinins: Human tachykinins with cardiovascular activity

Characterization of the endokinins: Human tachykinins with cardiovascular activity

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Hemokinin-1 Activates the MAPK Pathway and Enhances B Cell Proliferation and Antibody Production

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