Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human hemokinin-1 (h HK-1) and its truncated form h HK-1(4-11) are mammalian tachykinin peptides encoded by the recently identified TAC4 gene in human, and the biological functions of these peptides have not been well investigated. In the present study, an attempt has been made to investigate the effects and mechanisms of action of h HK-1 and h HK-1(4-11) in pain modulation at the supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of h HK-1 (0.3, 1, 3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the NK(1) receptor antagonist SR140333, but not by the NK(2) receptor antagonist SR48968, indicating that the analgesic effect induced by i.c.v. h HK-1 is mediated through the activation of NK(1) receptors. Interestingly, naloxone, beta-funaltrexamine and naloxonazine, but not naltrindole and nor-binaltorphimine, could also block the analgesic effect markedly, suggesting that this effect is related to descending mu opioidergic neurons (primary mu(1) subtype). Human HK-1(4-11) could also induce a dose- and time-dependent analgesic effect after i.c.v. administration, however, the potency of analgesia was less than h HK-1. Surprisingly, SR140333 could not modify this analgesic effect, suggesting that this effect is not mediated through the NK(1) receptors like h HK-1. SR48968 could modestly enhance the analgesic effect induced by h HK-1(4-11), indicating that a small amount of h HK-1(4-11) may bind to NK(2) receptors. Furthermore, none of the opioid receptor (OR) antagonists could markedly block the analgesia of h HK-1(4-11), suggesting that the analgesic effect is not mediated through the descending opioidergic neurons. Blocking of delta ORs significantly enhanced the analgesia, indicating that delta OR is a negatively modulatory factor in the analgesic effect of h HK-1(4-11). It is striking that bicuculline (a competitive antagonist at GABA(A) receptors) effectively blocked the analgesia induced by h HK-1(4-11), suggesting that this analgesic effect is mediated through the descending inhibitory GABAergic neurons. The novel mechanism involved in the analgesic effect of h HK-1(4-11), which is different from that of h HK-1, may pave the way for a new strategy for the investigation and control of pain.
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PMID:In vivo characterization of the effects of human hemokinin-1 and human hemokinin-1(4-11), mammalian tachykinin peptides, on the modulation of pain in mice. 1826 87

The tachykinins are a group of related peptides that are mainly synthesized in the central and peripheral nervous system, but are also present in peripheral non-neuronal cells. In humans, substance P (SP) is the most extensively studied tachykinin and is present, along with the NK-1 receptor, in several inflammatory and immune cells. The release of SP under the appropriate stimulus may act as a paracrine or autocrine signal that may help to initiate and/or propagate inflammation. In the present study we have determined the expression pattern of NKB and HK-1 mRNA in human lymphocytes, monocytes, neutrophils and eosinophils. In addition, we have detected for the first time the presence of NKB protein in these cellular types. These findings reinforce the suggestion that tachykinins play a central role in the pathophysiology of the inflammatory process.
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PMID:Differential expression of neurokinin B and hemokinin-1 in human immune cells. 1840 Mar 9

Substance P is a tachykinin that enhances pathways of inflammation. Leukocytes at sites of intestinal inflammation make substance P. This study explored the role of interleukin-12 (IL-12), IL-23, and the regulatory cytokines IL-10 and transforming growth factor beta (TGF-beta) in controlling leukocyte substance P production. In murine schistosomiasis, it was found that IL-12 and IL-23 drive substance P gene expression and peptide synthesis in murine splenic T cells and macrophages, respectively. Cytokine induction of substance P synthesis both in T cells and in macrophages depends on intracellular NF-kappaB activation and is Stat4 independent. IL-10 inhibits T-cell substance P production, while TGF-beta blocks macrophage substance P expression. Intestinal macrophages also produce substance P, subject mostly to IL-23 and TGF-beta regulation. Hemokinin is another tachykinin with homology to substance P. Macrophages and T cells make hemokinin, but hemokinin production is not subject to IL-12 or IL-23 regulation.
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PMID:Interleukin-12 (IL-12) and IL-23 induction of substance p synthesis in murine T cells and macrophages is subject to IL-10 and transforming growth factor beta regulation. 1850 13

The mammalian tachykinins are a family of closely related peptides including substance P, neurokinin A, neurokinin B and, recently, also hemokinin-1. They are present in the peripheral and central nervous systems, and bind to three known neurokinin (NK) receptors, the NK(1)-, NK(2)- and NK(3) receptors. In both rodents and humans, NK(3) receptors are expressed in brain structures which have been associated with learning and memory. Evidence for a role of NK(3) receptors in learning and memory has been found in NK(3) receptor knockout mice. Here, we investigated the influence of the NK(3) receptor agonist, senktide (0.1, 0.2 and 0.4 mg/kg), on the performance of C57BL/6 mice in a recently developed episodic-like memory task. Since a promnestic effect of senktide was expected, we employed an experimental protocol that provided sub-optimal learning conditions for episodic-like memory. The results indicate that senktide promotes episodic-like memory in mice in a dose-dependent manner, providing, for the first time, evidence for an involvement of NK(3) receptors in episodic-like memory.
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PMID:NK(3) receptor agonism promotes episodic-like memory in mice. 1855 25

Human hemokinin-1 and its carboxy-terminal fragment human hemokinin-1(4-11) have been recently identified as the members of the tachykinin family. The peripheral cardiovascular effects of these two tachykinin peptides were investigated in anesthetized rats. Lower doses of human hemokinin-1 (0.1-3 nmol/kg) injected intravenously (i.v.) induced depressor response, whereas higher doses (10 and 30 nmol/kg) caused biphasic (depressor and pressor) responses. The depressor response is primarily due to the action on endothelial tachykinin NK(1) receptor to release endothelium-derived relaxing factor (NO) and vagal reflex was absent in this modulation. The pressor response is mediated through the activation of tachykinin NK(1) receptor to release catecholamines from sympathetic ganglia and adrenal medulla. Moreover, human hemokinin-1 injected i.v. produced a dose-dependent tachycardia response along with blood pressure responses and the activation of sympathetic ganglia and adrenal medulla are involved in the tachycardia response. Human hemokinin-1(4-11) only lowered mean arterial pressure dose-dependently (0.1-30 nmol/kg) and the mechanisms involved in the depressor response are similar to that of human hemokinin-1. Additionally, human hemokinin-1(4-11) could also produce tachycardia response dose-dependently and the mechanisms involved in the tachycardia response are similar to that of human hemokinin-1 except that bilateral adrenalectomy could not affect the tachycardia markedly, indicating that the tachycardia induced by human hemokinin-1(4-11) is primarily due to the stimulation of sympathetic ganglia. In a word, to a certain extent, human hemokinin-1(4-11) is the active fragment of human hemokinin-1, however, the differences between human hemokinin-1 and hemokinin-1(4-11) involved in the effects of cardiovascular system suggest that the divergent amino acid residues at the N-terminus of human hemokinin-1 produced different activation properties for tachykinin NK(1) receptor.
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PMID:Cardiovascular responses to intravenous administration of human hemokinin-1 and its truncated form hemokinin-1(4-11) in anesthetized rats. 1858 57

The preprotachykinin gene Tac4 expressed in murine uterus and placenta is thought to encode a peptide RSRTRQFYGLM-NH(2), mouse hemokinin 1. We have examined the uterotonic effects of mouse hemokinin 1 and its N-terminally truncated analogue, mouse hemokinin 1(2-11) on mouse uterus. Mouse hemokinin 1(2-11) was equieffective with but slightly less potent than substance P in tissues from non-pregnant Swiss mice. On myometrium from Balb C mice primed with oestrogen the positions of concentration-response curves to substance P and the mouse hemokinins were similar to those of neurokinin A, but the maximum responses were lower. The tachykinin NK(1) receptor antagonist, 1-{2-(3, 4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl) piperidin-3-yl]ethyl}-4phenyl-1-azonia-bicyclo[2.2.2]octane (SR 140333), reduced the effects of the agonists in tissues from both groups of mice. In myometria from late pregnant (Days 17-18) Balb C mice the responses to mouse hemokinin 1(2-11) were less potent than in those from oestrogen-primed mice. Human hemokinin 1, the human orthologue of mouse hemokinin 1, was more effective than mouse hemokinin 1(2-11), while endokinin D was inactive. Mouse hemokinin 1 effects were blocked by SR 140333 alone and in combination with ((S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide (SR 48968) but not by SR 48968 alone. Thus the mouse hemokinins are tachykinin NK(1) receptor-preferring uterotonic agonists in non-pregnant mice but lack action at the myometrial tachykinin NK(2) receptors present in late pregnant mice.
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PMID:Functional characterisation of hemokinin-1 in mouse uterus. 1897 17

Dendritic cells (DCs) are the preferred targets for immunotherapy protocols focused on stimulation of cellular immune responses. However, regardless of initial promising results, ex vivo generated DCs do not always promote immune-stimulatory responses. The outcome of DC-dependent immunity is regulated by proinflammatory cytokines and neuropeptides. Proinflammatory neuropeptides of the tachykinin family, including substance P (SP) and hemokinin-1 (HK-1), bind the neurokinin 1 receptor (NK1R) and promote stimulatory immune responses. Nevertheless, the ability of pro-inflammatory tachykinins to affect the immune functions of DCs remains elusive. In the present work, we demonstrate that mouse bone marrow-derived DCs (BMDCs) generated in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4), express functional NK1R. Signaling via NK1R with SP, HK-1, or the synthetic agonist [Sar(9)Met(O(2))(11)]-SP rescues DCs from apoptosis induced by deprivation of GM-CSF and IL-4. Mechanistic analysis demonstrates that NK1R agonistic binding promotes DC survival via PI3K-Akt signaling cascade. In adoptive transfer experiments, NK1R-signaled BMDCs loaded with Ag exhibit increased longevity in draining lymph nodes, resulting in enhanced and prolonged effector cellular immunity. Our results contribute to the understanding of the interactions between the immune and nervous systems that control DC function and present a novel approach for ex vivo-generation of potent immune-stimulatory DCs.
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PMID:Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity. 1898 61

The preprotachykinin C gene encodes four endokinins, A, B, C, and D. Endokinins A and B and substance P (SP) are typical tachykinin peptides since their carboxyl-terminal regions share an F-F-G-L-M-amide, while endokinins C and D share an F-Q-G-L-L-amide. It is demonstrated that pretreatment with a peptide consisting of a common sequence between endokinins C and D (EKC/D) attenuates the induction of scratching behavior and thermal hyperalgesia by intrathecal administration of SP or EKA/B (the carboxyl-terminal dacapeptide common in endokinins A and B), suggesting that leucine at the carboxyl-terminal of EKC/D may have a crucial role in eliciting these effects. When the effect of [Leu(11)]-SP and [Leu(10)]-EKA/B on SP-induced pain-related behavior was examined, the induction of pain-related behavior was markedly attenuated by pretreatment with these peptides. This indicates that leucine at the carboxyl-terminal of these peptides plays a crucial role in eliciting this antagonistic effect.
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PMID:Effect of the carboxyl-terminal of endokinins on SP-induced pain-related behavior. 1899 86

Hemokinin-1, encoded by the TAC4 gene, is the most recent addition to the tachykinin family. Although most closely related to the neuropeptide Substance P, Hemokinin-1 distinguishes itself from other tachykinins by its predominantly non-neuronal expression pattern. Its expression in T and B lymphocytes, macrophages, and dendritic cells points to an important role for Hemokinin-1 in the immune system. To seek reasons for its preferential expression in the immune system and ultimately to provide clues to its function, we investigated the molecular mechanisms driving the differential expression pattern of this unique tachykinin. Our study provides the first analysis of the promoter region of the TAC4 gene, which reveals regulatory mechanism different from the Substance P promoter. We demonstrate for the first time that Hemokinin-1 initiates transcription from multiple start sites through a TATA-less promoter. Conservation of the 5' non-coding region indicates the importance of the upstream regulatory region in directing expression of Hemokinin-1 in specific cell types, during cell differentiation and activation. Furthermore, NFkappaB, a transcription factor important in the activation of immune cells was shown to be involved in promoting increased TAC4 transcription during PMA induction of a T cell line. Our studies reveal that Hemokinin-1 is regulated by a unique transcription regulation system that likely governs its differential expression pattern and suggests a role for Hemokinin-1 distinct from Substance P.
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PMID:Regulatory mechanisms in the differential expression of Hemokinin-1. 1908 Nov 34

Rat/mouse hemokinin-1 (r/m HK-1) has been identified as a member of the tachykinin family and its effect in colonic contractile activity remains unknown. We investigated the effects and mechanisms of actions of r/m HK-1 on the mouse colonic contractile activity in vitro by comparing it with that of substance P (SP). R/m HK-1 induced substantial contractions on the circular muscle of mouse colon. The maximal contractile responses to r/m HK-1 varied significantly among proximal-, mid- and distal-colon, suggesting that the action of r/m HK-1 was region-specific in mouse colon. The contractile response induced by r/m HK-1 is primarily via activation of tachykinin NK(1) receptors leading to activation of cholinergic excitatory pathways and with a minor contribution of NK(2) receptors, which may be on the smooth muscle itself. A direct action on colonic smooth muscles may be also involved. In contrast, SP induced biphasic colonic responses (contractile and relaxant responses) on the circular muscle, in which the contractile action of SP was equieffective with r/m HK-1. SP exerted its contractile effect predominantly through neural and muscular tachykinin NK(1) receptors, but unlike r/m HK-1 did not appear to act via NK(2) receptors. The relaxation induced by SP was largely due to release of nitric oxide (NO) produced via an action on neural NK(1) receptors. These results indicate that the receptors and the activation properties involved in r/m HK-1-induced mouse colonic contractile activity are different from those of SP.
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PMID:In vitro characterization of the effects of rat/mouse hemokinin-1 on mouse colonic contractile activity: a comparison with substance P. 1939 90


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