UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian tachykinin receptors belong to the family of G protein-coupled receptors and consist of the substance P, substance K and neuromedin K receptors (SPR, SKR and NKR). We constructed 14 chimeric receptors in which seven transmembrane segments were sequentially exchanged between the rat SPR and SKR and examined the subtype specificity of the chimeric receptors by radioligand binding and inositol phosphate measurements after transfection into COS cells. All chimeric receptors showed maximum responses in agonist-induced inositol phosphate stimulation. Detailed analysis of five receptors with agonist selectivity similar to SPR indicated that the selectivity is mainly determined by the region extending from transmembrane segment II to the second extracellular loop together with a minor contribution of the extracellular N-terminal portion. This conclusion was more directly confirmed by an additional chimeric formation in which the introduction of the above middle portion of SPR into the corresponding region of SKR conferred a high affinity binding to substance P. The tachykinin receptors can thus be divided into two functional domains: the region covering transmembrane segments V-VII and responsible for fundamental recognition of the common tachykinin sequence; and its preceding portion involved in evoking subtype specificity by interacting with the divergent sequences of the peptides.
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PMID:Delineation of structural domains involved in the subtype specificity of tachykinin receptors through chimeric formation of substance P/substance K receptors. 138 77

The activities of two groups of cyclic agonists of substance P (SP) have been studied. The disulfide bridge constraints have been designed on the basis of conformational studies on SP and physalaemin indicating an alpha-helical structure for the core of these two tachykinins (group I) and a folding of the C-terminal carboxamide towards the side chains of the glutamines 5 and 6 (group II). Only peptides simulating the alpha-helix present substantial potencies. [Cys3,6]SP is as active as SP in inhibiting 125I-labeled Bolton and Hunter SP-specific binding on rat brain synaptosomes and on dog carotid bioassay, two assays specific for the neurokinin 1 receptor. Moreover, [Cys3,6]SP is as potent as neurokinin B in inhibiting 125I-labeled Bolton and Hunter eledoisin-specific binding on rat cortical synaptosomes as well as in stimulating rat portal vein, two tests specific for the neurokinin 3 receptor. Interestingly, in contrast to neurokinin B, [Cys3,6]SP is a weak agonist of the neurokinin 2 receptor subtype, as evidenced by its binding potency in inhibiting 3H-labeled neurokinin A-specific binding on rat duodenum and in inducing the contractions of the rabbit pulmonary artery, a neurokinin 2-type bioassay. To increase the specificity of the cyclic analogue [Cys3,6]SP positions 8 and 9 were modified. [Cys3,6, Tyr8, Ala9]SP is slightly less selective than SP for the neurokinin 1 receptor subtype. [Cys2,5]neurokinin B constitutes a selective cyclic agonist for the neurokinin 3 receptor. The very weak potencies of the peptides from group II indicate that a certain degree of flexibility in the C-terminal moiety is required. Collectively, these results suggest that the neurokinin 1 and neurokinin 3 tachykinin receptors may recognize a similar three-dimensional structure of the core of the tachykinins. Different orientations of the common C-terminal tripeptide may be related to the selectivity for the different receptor subtypes.
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PMID:Interaction of tachykinins with their receptors studied with cyclic analogues of substance P and neurokinin B. 244 17

Substance P (SP) is a neuropeptide widely distributed in the nervous system. Its release within the bone marrow (BM) can mediate bidirectional neurohematopoietic communication via specific receptors: neurokinin-1R (NK-1R), NK-2R, or NK-3R. We have previously reported that SP effects on hematopoiesis are mediated by an NK-1-type receptor, the BM stroma, and growth factors. Here, we have studied the induction of stem cell factor (SCF) and interleukin-1 (IL-1) by SP in stroma. At 10(-9) mol/L SP, cytokine levels in supernatants were IL-1 alpha, 20 +/- 5 ng/mL; IL-1 beta, 40 +/- 10 ng/mL; and SCF, nondetectable; and the cell-associated levels were SCF, 21 +/- 2 ng/mL; IL-1 alpha, 90 +/- 6 ng/mL; and IL-1 beta, 45 +/- 3 ng/mL. Reverse transcriptase-polymerase chain reaction and ligand-binding studies with stroma stimulated by these two cytokines resulted in (1) NK-1-like receptor mRNA accumulation and (2) downregulation of SP binding sites (day 1) followed by an upregulation (day 3). Low numbers of high-affinity receptors were expressed by day 1 but not by day 3. The results indicate that SP induces IL-1 and SCF in stroma and that these cytokines have the potential to autoregulate NK-R.
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PMID:Substance P (SP) mediates production of stem cell factor and interleukin-1 in bone marrow stroma: potential autoregulatory role for these cytokines in SP receptor expression and induction. 754 64

Substance P has several inflammatory effects on the airways mediated via neurokinin 1 receptors (NK1Rs) and, if released from sensory nerves, may amplify the chronic inflammation seen in asthma. Northern blot analysis of NK1R mRNA in lung showed a 52 +/- 10% (S.E.M.; P < 0.01) increase in mRNA in the asthmatic lung compared with non-asthmatic control tissue. NK1R mRNA was reduced by 84.5 +/- 1.9% after incubation with dexamethasone (1 microM) for 3 h (P < 0.01). In contrast, NK2R mRNA was unaltered in asthmatic lungs and dexamethasone treatment had no effect on the level of NK2R mRNA. These results suggest that chronic inflammation in asthma may result in increased NK1R gene expression and that this effect is reversed by glucocorticosteroids.
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PMID:Increased tachykinin receptor gene expression in asthmatic lung and its modulation by steroids. 824 Jun 67

The tachykinins are a family of neuropeptides that share a common carboxyl terminus. Substance P (SP) and neurokinin-A (NK-A) are derived from the preprotachykinin l gene. Although SP and NK-A can bind to either NK-1, NK-2, or NK-3 receptors (R), they have preferences for NK-1R and NK-2R, respectively. We have reported that SP stimulates erythroid (E) (burst-forming unit [BFU]-E and colony-forming unit [CFU]-E) and myeloid (CFU-granulocyte-macrophage [GM]) progenitors partly through the induction of growth factors. We have now investigated the hematopoietic effects of NK-A using short-term bone marrow (BM) cultures and found that NK-A (10(-7) to 10(-12) mol/L) inhibits CFU-GM proliferation but stimulates erythroid progenitors. Release of soluble factors by the stroma appears to mediate the inhibition because direct contact with the stroma was not required. We have found that NK-A, through NK-2-like receptors induces increased levels of macrophage inflammatory protein-1 alpha (MIP-1 alpha) and transforming growth factor-beta (TGF-beta) (transcriptional and posttranscriptional) in BM stroma. Clonogenic assays with NK-A (10(-9) mol/L) and either anti-MIP-1 alpha or anti-TGF- beta 1 indicate that these cytokines partly contribute to the inhibition, suggesting that these two negative hematopoietic regulators exert part of the inhibition by NK-A on CFU-GM. The findings of two closely related neuropeptides, derived from the same gene, exerting opposite effects on myeloid colonies suggest that neuropeptides, by themselves could be important factors in hematopoietic regulation.
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PMID:Induction of negative hematopoietic regulators by neurokinin-A in bone marrow stroma. 870 7

We have been studying hematopoietic effects by the tachykinins, which like many other neuropeptides can be expressed in neural and nonneural tissues. Substance P (SP) and neurokinin-A (NK-A), members of the tachykinins are immune and hematopoietic modulators. SP and NK-A are derived from the preprotachykinin-I gene (PPT-I) through alternate splicing and posttranslational modification. In the bone marrow (BM), nerve fibers provide a source of neural SP and the stroma provides a source of nonneural SP. The tachykinins interact with each of three cloned neurokinin (NK) receptors (NK-1R, NK-2R, NK-3R) with SP and NK-A exhibiting binding preferences for NK-1R and NK-2R, respectively. Proliferation of myeloid progenitors (CFU-GM) is differentially regulated by SP and NK-A. The former enhances the proliferation whereas the latter is inhibitory. The BM stroma mediates most of the hematopoietic effects exerted by SP and NK-A partly through the induction of cytokines. The proliferative effects of SP correlate with the induction of positive hematopoietic growth factors such as IL-3, IL-6, GM-CSF and c-kit ligand and the inhibitory effects by NK-A correlate with the induction of two negative hematopoietic regulators, MIP-1 alpha and TGF-beta. Intracellular signals mediated by NK-1R and NK-2R are part of the mechanism responsible for tachykinin-mediated regulation of hematopoiesis. The stimulatory effects on BM progenitors mediated by NK-1R can be partly inhibited by NK-2R activation. IL-1 and other cytokines induced by SP in BM stroma modulate NK-1R induction. Furthermore, SP can induce IL-1 type I receptor in stroma. Together, these data suggest that the tachykinins and the cytokines interact to regulate hematopoiesis. These interactions contribute to hematopoietic regulation by mechanisms that involve induction of: (1) tachykinins and cytokines by each other; (2) NK-1R by cytokines and (3) cytokine receptor by the tachykinins. These studies emphasize that in terms of hematopoiesis, the cytokines and neuropeptides are not mutually exclusive factors and thus, the hematopoietic regulatory network would be incomplete without the role of neuropeptides being considered.
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PMID:Hematopoietic modulation by the tachykinins. 928

Stimulation of the cornea activates neurons in two distinct regions of the spinal trigeminal nucleus: at the transition between trigeminal subnucleus interpolaris and subnucleus caudalis and at the transition between trigeminal subnucleus caudalis and the upper cervical spinal cord as estimated by expression of the immediate early gene, c-fos. To determine if receptors for substance P or neurokinin A, neurokinin 1 and neurokinin 2 receptors, respectively, contribute to the production of Fos-positive neurons in these brainstem regions, receptor-selective antagonists were given intracerebroventricularly 15 min prior to stimulation of the cornea in anesthetized rats. The number of Fos-positive neurons produced in superficial laminae at the trigeminal subnucleus caudalis/cervical cord transition by application of the selective small fiber excitant, mustard oil, to the corneal surface was reduced by the neurokinin 1 receptor antagonist, CP99,994 (5-100 nmol, i.c.v.) and the neurokinin 2 receptor antagonist, MEN10,376 (0.01-1.0 nmol, i.c.v.). Combined pretreatment with CP99,994 and the competitive N-methyl-D-aspartate receptor antagonist, CPP, caused a greater reduction in c-fos expression at the subnucleus caudalis/cervical cord transition than after either drug alone suggesting interaction between receptors for glutamate and substance P. Tachykinin receptor antagonists did not reduce the number of Fos-positive neurons produced at the subnucleus interpolaris/subnucleus caudalis transition. The elevation in plasma concentration of adrenocorticotropin, but not the increases in arterial pressure or heart rate, evoked by corneal stimulation was prevented by pretreatment with CP99,994 or MEN10,376 at doses lower than those needed to reduce c-fos expression. The results indicate that receptors for substance P and neurokinin A contribute to the transmission of sensory input from corneal nociceptors to brainstem neurons in trigeminal subnucleus caudalis and to increased activity of the hypothalamo-pituitary axis that accompanies acute stimulation of the cornea.
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PMID:Selective blockade of substance P or neurokinin A receptors reduces the expression of c-fos in trigeminal subnucleus caudalis after corneal stimulation in the rat. 946 Jul 60

The use-dependent increase in synaptic strength between primary afferent C-fibres and second-order neurons in superficial spinal dorsal horn may be an important cellular mechanism underlying central hyperalgesia. This long-term potentiation can be blocked by antagonists of the N-methyl-D-aspartate subtype of glutamate receptor, the neurokinin 1 or the neurokinin 2 receptor. We have tested here whether activation of these receptors by superfusion of the spinal cord with corresponding agonists in the absence of presynaptic activity is sufficient to induce long-term potentiation. In urethane anaesthetized rats C-fibre-evoked field potentials were elicited in superficial laminae of lumbar spinal cord by electrical stimulation of the sciatic nerve. In rats with intact spinal cord, controlled superfusion of the spinal cord at recording segments for 60 min with N-methyl-D-aspartate, substance P or neurokinin A never induced long-term potentiation. Spinal superfusion with a mixture of N-methyl-D-aspartate, substance P and neurokinin A also failed to induce long-term potentiation in four rats tested. In spinalized rats, however, long-term potentiation was induced by either N-methyl-D-aspartate (at 10 microM, to 173 +/- 16% of control) substance P (at 10 microM, to 176 +/- 13% of control) or by neurokinin A (at 1 microM, to 198 +/- .20% of control). The induction of long-term potentiation by N-methyl-D-aspartate, substance P or neurokinin A was blocked by intravenous application of the receptor antagonists dizocilpine maleate (0.5 mg/kg), RP67580 (2 mg/kg) or SR48968 (0.2 mg/kg), respectively. Thus, activation of N-methyl-D-aspartate or neurokinin receptors may induce long-lasting plastic changes in synaptic transmission in afferent C-fibres and this effect may be prevented by tonic descending inhibition.
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PMID:Activation of spinal N-methyl-D-aspartate or neurokinin receptors induces long-term potentiation of spinal C-fibre-evoked potentials. 969 27

There is increasing evidence that sensory nerves may participate in cutaneous inflammatory responses by the release of neuropeptides such as substance P (SP). We examined the direct effect of SP on human dermal microvascular endothelial cell (HDMEC) intercellular adhesion molecule 1 (ICAM-1) expression and function. Our results indicated that, although cultured HDMEC expressed mRNA for neurokinin receptors 1, 2, and 3 (NK-1R, NK-2R, and NK-3R), SP initiated a rapid increase in HDMEC intracellular Ca2+ levels, primarily by the activation of NK-1R. Immunohistochemistry studies likewise demonstrated that HDMEC predominantly expressed NK-1R. The addition of SP to HDMEC resulted in a rapid increase in cellular ICAM-1 mRNA levels, followed by a fivefold increase in ICAM-1 cell surface expression. This functionally resulted in a threefold increase in 51Cr-labeled binding of J-Y lymphoblastoid cells to HDMEC. In vivo studies demonstrated a marked increase in microvascular ICAM-1 immunostaining 24 and 48 h after application of capsaicin to the skin. These results indicate that neuropeptides such as SP are capable of directly activating HDMEC to express increased levels of functional ICAM-1 and further support the role of the cutaneous neurological system in modulating inflammatory processes in the skin.
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PMID:Neuropeptide regulation of human dermal microvascular endothelial cell ICAM-1 expression and function. 984 20

Substance P (SP) is a neuropeptide widely distributed in the nervous system. Extensive study has shown SP stimulates production of various cytokines by bone marrow stromal cells, although, the role of SP in hematopoietic phenomena is still unclear. Recently, we established a human cloned stromal cell line, HAS303, which can support hematopoietic stem cell proliferation and differentiation in vitro. We used this culture system to examine the effects of SP. Expression of the mRNAs of neurokinin (NK)-1R, NK-2R and NK-3R, specific SP receptors, on HAS303 cells was demonstrated by the RT-PCR. CD34+ cells isolated from bone marrow were co-cultivated with HAS303 cells in the presence and absence of SP and the total hematopoietic cells and progenitors were counted every 5 days. Introducing SP (10(-8) M) to the co-cultures significantly increased the number of total cells and progenitors compared with control cultures. SP showed no enhancing activity on CD34+ cells cultured alone. SP also stimulated IL-3-dependent colony formation of whole bone marrow MNCs in a soft agar culture system, but showed no such activity on isolated CD34+ cells in this system. These observations suggest that SP stimulated HAS303 cells, activated HAS303 cells, and stimulated the proliferation and differentiation of CD34+ cells. Treating HAS303 cells with SP increased the intracellular Ca2+ concentration and stimulated production of G-CSF, GM-CSF, SCF and IL-6, but not IL-1alpha, IL-1beta and TNF-alpha, but did not enhance proliferation. All these findings suggest that SP mediates hematopoietic cell proliferation and differentiation in vitro by activating stromal cell function.
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PMID:Stimulatory effects of substance P on CD34 positive cell proliferation and differentiation in vitro are mediated by the modulation of stromal cell function. 985 36

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