UNIPROT:P20366 - FACTA Search

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)

Endokinins are novel mammalian tachykinin peptides designated from a human preprotachykinin gene and consist of endokinin A (EKA), endokinin B (EKB), endokinin C (EKC) and endokinin D (EKD). A representative of the tachykinin peptide is substance P (SP), which functions as a pain modulator or transmitter and contributes to pain processing; however, little is known about the function of endokinins in pain processing. Therefore, we evaluated the effects of EKA/B (using the common C-terminal decapeptide in EKA and EKB) and EKC/D (using the common C-terminal duodecapeptide in EKC and EKD) on pain processing in rats. Intrathecal administration of 10(-3) M (10 nmol) EKA/B evoked pain-related behavior such as scratching while 10(-3) M EKC/D administration did not. This induction of scratching behavior following EKA/B administration was suppressed by pretreatment with an NK1 receptor antagonist. In addition to the induction of scratching behavior, intrathecal administration of 10(-7) - 10(-4) M (1 pmol-1 nmol) EKA/B decreased the latency of the paw withdrawal response to noxious thermal stimulation, whereas there was little effect of EKC/D administration on the latency of the withdrawal response. This effect of EKA/B was also suppressed by pretreatment with NK1 receptor antagonists. These results indicate that intrathecal administration of EKA/B but not EKC/D evokes scratching behavior and thermal hyperalgesia through the NK1 receptor.
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PMID:Intrathecal administration of the common carboxyl-terminal decapeptide in endokinin A and endokinin B evokes scratching behavior and thermal hyperalgesia in the rat. 1710 Dec 18

The related immunomodulatory neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP; gene symbol ADCYAP1) have recently been proposed as novel therapeutics for the treatment of multiple sclerosis (MS). These neuropeptides, as well as those belonging to the tachykinin family exert pleiotropic effects, many of which are of relevance to central nervous system inflammation. In the present study, we have analysed 14 single nucleotide polymorphisms (SNPs) and 4 microsatellite markers in the VIP, ADCYAP1, TAC3 and TAC4 genes for susceptibility to MS in a case-control collection from Northern Ireland. Following correction for multiple comparisons, we did not find any significant associations between single polymorphic markers or multiple-marker haplotypes and susceptibility to MS. Furthermore, we analysed 2 SNPs in the TAC1 gene in a set of Sardinian trio MS families, based on our previous observation of association of these SNPs with MS in the Northern Irish (Genes Immun. 2005, 6, 265-270). Analysis of these SNPs in the Sardinians was not significant though a similar trend to that originally observed in the Northern Irish was present. Meta-analysis of the Sardinian and Northern Irish TAC1 SNP genotype data revealed a Mantel-Haenszel Common OR Estimate for the TAC1 intron 1 SNP rs2072100 of 0.76 (95% CI 0.63-0.92; P=0.005; A allele) and for the TAC1 promoter SNP rs7793277 of 0.76 (95% CI 0.615-0.95; P=0.014; C allele). Our data advocate a need for further exploration of the TAC1 gene region in MS.
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PMID:The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis. 1717 32

Some novel tachykinin peptides exhibiting homology with known members of the tachykinin family have been recently reported; however, little is known about the function of these peptides. Repeated intrathecal administration of substance P (SP) causes desensitization by binding SP to neurokinin 1 (NK1) receptor. Thus, to clarify the characteristics of the receptors involved in these novel peptides, we investigated whether desensitization is induced by intrathecal administration of these peptides in rats since desensitization is induced by binding these peptides to the receptor. Intrathecal administration of 10(-3) M hemokinin-1 (HK-1) and 10(-3) M decapeptide common in the carboxyl-terminal region of endokinin A and endokinin B (EKA/B) as well as SP evoked scratching behavior. When each peptide was administered twice with an interval of 15 min, remarkable desensitization of scratching behavior was produced. Furthermore, the first administration of EKA/B or SP produced clear cross-desensitization to SP, EKA/B and HK-1, whereas the first administration of HK-1 demonstrated weak cross-desensitization to EKA/B and SP. These results suggest that EKA/B and SP may bind to both the NK1 receptor and HK-1-preferred receptor, and HK-1 may preferentially bind to its preferred receptor.
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PMID:The common carboxyl-terminal region of novel tachykinin peptides contributes to induce desensitization in scratching behavior of rats. 1725 14

Hematopoiesis is the process by which a limited number of hematopoietic stem cells (HSCs) maintain a functioning blood and immune system. In adults, hematopoiesis occurs in bone marrow and is supported by the microenvironment. The tachykinin family of peptides regulates hematopoiesis. Tachykinins can be released in bone marrow as neurotransmitters from innervating fibers, and from resident bone marrow cells. The hematopoietic effects by tachykinins involve four tachykinin genes, Tac1-Tac4. The latter is the most recently discovered member and encodes hemokinin-1, endokinin A, endokinin B, and two orphan peptides, endokinin C, and endokinin D. The alteration of normal hematopoietic functions by the tachykinins may result in the development of various pathologies. For example, Tac1 is involved in myelofibrosis and in leukemia, both of which are dysfunction of hematopoietic stem cells. A comprehensive understanding of dysfunctions caused by the tachykinins requires further research since other cells, such as stromal cells and factors including cytokines, chemokines, and endopeptidases, are involved in a network in which the tachykinins have critical roles. Studies into the properties and functions of tachykinins, the biology of their receptors, and related molecules would provide insights into the development of aging disorders, hematopoiesis, other dysfunction, and may also lead to the discovery of novel and effective clinical therapies. Controversies on applications for hematopoietic stem cells in regenerative medicine are discussed. Despite these controversies, a detailed understanding on how the bone marrow microenvironment maintains pluripotency of hematopoietic stem cells would be useful to manipulate the system to acquire specialized cells for tissue repair.
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PMID:Tachykinins and hematopoietic stem cell functions: implications in clinical disorders and tissue regeneration. 1748 13

Rat and mouse hemokinin-1(r/m hemokinin-1) is a recently described member of the tachykinin family whose cardiovascular functions are not fully understood. In this study, we investigated the mechanisms of the relaxing response induced by r/m hemokinin-1 in isolated porcine coronary arteries by using a specific antagonist of tachykinin NK(1) receptor (SR140333), a nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (L-NNA), and 1H-[1,2,4] Oxadiazolo [4,3-a] quinoxalin-1-one (ODQ), a blocker of cGMP production. r/m Hemokinin-1 (10(-12)-10(-6 )M) evoked a marked endothelium-dependent vasodilatation (E(max)=121.12+/-10.6% and 91.79+/-2.39% in 10(-6) M PGF(2)alpha and 30 mM KCl precontracted arterial rings, respectively) 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 vasorelaxation as a compensatory mechanism.
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PMID:Mechanisms of relaxing response induced by rat/mouse hemokinin-1 in porcine coronary arteries: roles of potassium ion and nitric oxide. 1756 Sep 93

Rat/mouse hemokinin-1 is a mammalian tachykinin peptide whose biological functions have not been well characterized. In the present study, an attempt has been made to investigate the effect and mechanism of action of rat/mouse hemokinin-1 on systemic arterial pressure after intravenous (i.v.) injections in anesthetized rats by comparing it with that of substance P. Our data showed that injection of rat/mouse hemokinin-1 (0.1, 0.3, 1, 3 and 10 nmol/kg) lowered systemic arterial pressure dose-dependently. This effect was significantly blocked by pretreatment with SR140333 (a selective tachykinin NK1 receptor antagonist) and the NO synthase inhibitor L-NAME (Nomega-nitro-L-arginine methyl ester hydrochloride), respectively, but was not affected by bilateral vagotomy or the muscarinic receptor blocker atropine. Compared to rat/mouse hemokinin-1, a dose of 3 nmol/kg of substance P caused biphasic changes in systemic arterial pressure (depressor and pressor responses). The results suggest that the mechanism of the depressor response caused by substance P was similar to rat/mouse hemokinin-1 in that it was inhibited by SR140333 and L-NAME, respectively, but that there was a component of the cardiovascular change induced by rat/mouse hemokinin-1 (but not substance P) that was attenuated by SR48968 (a selective tachykinin NK2 receptor antagonist). The depressor response induced by rat/mouse hemokinin-1 (i.v.) might be explained primarily by the action on endothelial tachykinin NK1 receptors to release endothelium-derived relaxing factor (NO) and this effect was not affected by vagal components. In addition, rat/mouse hemokinin-1 could not induce the pressor response through stimulation of sympathetic ganglion like substance P in anesthetized rats.
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PMID:Cardiovascular responses to rat/mouse hemokinin-1, a mammalian tachykinin peptide: systemic study in anesthetized rats. 1762 23

Endokinins are tachykinin peptides designated from a human preprotachykinin C (PPT-C, TAC4) gene and consist of endokinin A (EKA), endokinin B (EKB), endokinin C (EKC) and endokinin D (EKD). A representative of mammalian tachykinins is substance P (SP), which functions as a neurotransmitter or modulator in the pain system; however, little is known about the role of these endokinins, especially EKC and EKD, in pain processing. Therefore, we evaluated the effects of EKC/D (using the common carboxyl-terminal duodecapeptide in EKC and EKD) on pain processing in rats. Pretreatment with EKC/D prevented induction of scratching behavior and thermal hyperalgesia by intrathecal administration of EKA/B (using the common C-terminal decapeptide in EKA and EKB) and SP and c-Fos expression in laminae I/II and V/VI of the spinal cord by noxious thermal stimulation. A prominent difference between EKC/D and SP is the presence of leucine instead of methionine at the carboxyl-terminal of EKC/D. Thus, to clarify whether leucine at the carboxyl-terminal of EKC/D plays an important role in determining the inhibitory effect of this peptide, we intrathecally administered [Met(12)]-EKC/D in which only leucine of EKC/D is replaced by methionine. This peptide did not exhibit the inhibitory effect on SP-induced scratching behavior or thermal hyperalgesia but conversely caused thermal hyperalgesia. Taken together, these findings indicate that EKC/D has an inhibitory effect on pain processing in the rat spinal cord, and the effect is due to leucine at the carboxyl-terminal of EKC/D.
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PMID:Leucine at the carboxyl-terminal of endokinins C and D contributes to elicitation of the antagonistic effect on substance P in rat pain processing. 1765 32

We have recently reported that rat/mouse hemokinin-1 (r/m HK-1), a mammalian tachykinin, produced dose- and time-related antinociceptive effects at the supraspinal level via activating NK(1) receptors. Moreover, r/m HK-1 remarkably enhanced both the antinociceptive extent and duration of morphine administered at the peripheral and supraspinal level through a convergence of pharmacological effects of opioid-responsive neurons. Pethidine hydrochloride is an important narcotic analgesic, which acts as an opiate agonist and has pharmacological effects similar to morphine. To improve our knowledge of the pharmacology of pethidine, the aim of the present study was to investigate the relationship between the nociception of r/m HK and pethidine by comparing it with that of r/m HK-1 and morphine. Our data showed that r/m HK-1 remarkably enhanced the antinociceptive extent of pethidine administered at the peripheral level, but not at the supraspinal level. These antinociceptive effects were blocked by prior treatment with the classical opioid receptor antagonist naloxone, indicating that the potentiated analgesic effect is mediated by opioid-responsive neurons. Differences in the antinociceptive activity of pethidine and morphine in combination with r/m HK-1, arise because there are differences in the physicochemical and pharmacokinetic properties of pethidine and morphine, particularly their lipophilicity. Our results may pave the way for a new strategy for the control of pain and may provide a clinical strategy to enable selection of either opioid as a priority.
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PMID:Effects of rat/mouse hemokinin-1, a mammalian tachykinin peptide, on the antinociceptive activity of pethidine administered at the peripheral and supraspinal level. 1767 56

Desensitization is induced by the repeated administration of high doses of substance P (SP) or hemokinin-1 (HK-1). However, little information is available about the mechanisms involved in the induction of desensitization by these peptides. Thus, to characterize this desensitization, we examined the dose-dependent effect of these peptides, the effect of pretreatment with neurokinin 1(NK1) receptor antagonists, and the effect of pretreatment with inhibitors of protein kinases such as protein kinase A (PKA), protein kinase C (PKC), calcium/calmodulin kinase II (CaMKII) and mitogen-activated protein kinase kinase (MEK). The number of scratchings induced by 10(-3)M SP or HK-1 decreased following pretreatment with 10(-11)-10(-3)M SP or HK-1 with a marked reduction at 10(-3) and 10(-6)M SP or HK-1. The effect of NK1 receptor antagonists on desensitization induced by pretreatment with 10(-6)M SP was marked, whereas there was little effect of pretreatment with these antagonists on 10(-6)M HK-1-induced desensitization. Additionally, 10(-6)M SP- and HK-1-induced desensitization was attenuated by pretreatment with PKA, PKC and MEK inhibitors, except a CaMKII inhibitor that inhibited SP-induced desensitization. These results indicate that the receptor and kinases involved in HK-1-induced desensitization are partially different from those of SP.
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PMID:Pharmacological characterization of desensitization in scratching behavior induced by intrathecal administration of hemokinin-1 in the rat. 1805 10

In the brain, tachykinins acting via the three cloned neurokinin (NK) receptors are implicated in stress-related affective disorders. Hemokinin-1 is a novel tachykinin that reportedly prefers NK1 to NK2 or NK3 receptors. Although NK1 and NK3 receptors are abundantly expressed in the brain, NK2-receptor-mediated electrophysiological effects have rarely been described as NK2 receptors are expressed only in a few brain regions such as the nucleus of the medial septum/diagonal band. Medial septal/diagonal band neurons that control hippocampal mnemonic functions also colocalize NK1 and NK3 receptors. Functionally, intraseptal activation of all three NK receptors increases hippocampal acetylcholine release and NK2 receptors have specifically been implicated in stress-induced hippocampal acetylcholine release. Electrophysiological studies on the effects of NKs on septohippocampal cholinergic neurons are lacking and electrophysiological effects of hemokinin-1 have thus far not been reported in brain neurons. In the present study we examined the electrophysiological and pharmacological effects of multiple NKs on fluorescently tagged septohippocampal cholinergic neurons using whole-cell patch-clamp recordings in a rat brain slice preparation. We demonstrate that a vast majority of septohippocampal cholinergic cells are activated by NK1, NK2 and NK3 receptor agonists as well as by hemokinin-1 via direct post-synaptic mechanisms. Pharmacologically, hemokinin-1 recruits not only NK1 but also NK2 and NK3 receptors to activate septohippocampal cholinergic neurons that are the primary source of acetylcholine for the hippocampus.
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PMID:Neurokinins robustly activate the majority of septohippocampal cholinergic neurons. 1818 16

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