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)

Substance P (SP) stimulates polyphosphoinositide breakdown in the rat anterior pituitary through an NK-1 receptor. In the present study we present evidence that the coupling between the SP-NK1 receptor complex and polyphosphoinositide-specific phospholipase C (PI-PLC) in rat anterior pituitary membranes may involve a mechanism consistent with a GTP-binding protein. The formation of inositol phosphates from [3H]myo-inositol-labelled anterior pituitary membranes induced by SP was potentiated by GTP and non-hydrolysable guanine nucleotides. The stimulatory effects of SP alone and SP plus GTP could be blocked by addition of GDP-beta-S (guanosine 5-O-(thiodiphosphate] in excess. Basal and SP plus guanine nucleotide-induced inositol phosphate formation were stimulated by fluoride, whereas the effect of SP alone was inhibited. Pretreatment of anterior pituitary membranes with sodium deoxycholate attenuated the inositol phosphate response elicited by GTP and GTP-gamma-S, whereas basal and SP-stimulated inositol phosphate production showed a peak at 1 mg sodium deoxycholate/ml. SP, fluoride and guanine nucleotide stimulatory effects on hydrolysis of polyphosphoinositide (PPI) were unaffected by pretreatment of anterior pituitary cells with cholera or pertussis toxin for 12h. Treatment of anterior pituitary membranes with cholera and pertussis toxin yielded [32P]ADP-ribosylation of two proteins with molecular masses of 45 and 41 kDa respectively. We conclude that SP coupling to PI-PLC through the NK1 receptor in the rat anterior pituitary involves a GTP-binding mechanism distinct from the G-proteins associated with adenylate cyclase, Gs and Gi.
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PMID:Substance P stimulation of polyphosphoinositide hydrolysis in rat anterior pituitary membranes involves a GTP-dependent mechanism. 171 80

An increase in inositol 1, 4, 5-trisphosphate (IP3) formation in rat mast cells precedes an elevation in intracellular Ca2+ levels, which triggers the process(es) leading to histamine release. By means of a transmission electron microscope, it was revealed that when permeabilized mast cells were exposed to potassium antimonate, antimonate precipitates in the endoplasmic reticulum (ER) in the form of calcium antimonate, indicating that the ER is the intracellular Ca store in rat mast cells. IP3 at concentrations higher than 0.5 microM preferentially releases Ca2+ from the isolated ER of mast cells. GTP was also effective in releasing Ca2+ from the ER. IP3-induced Ca2+ release was inhibited by pretreatments with cAMP and antiallergic drugs. An increase in the intracellular Ca2+ concentration may lead to an activation of calmodulin, C kinase and cytoskeletal elements in sequence. Furthermore, microtubules may play an important role in the process(es) leading to Ca2+ release from the intracellular Ca store and subsequent histamine release, without affecting IP3 formation. In contrast, microfilaments seem to participate not only in the extrusion but also in the reincorporation of the mast cell granules, having no influence on intracellular Ca2+ release. Substance P (SP) is one of the most effective neuropeptides for releasing histamine from mast cells. Structure-activity relationship studies indicate that basicity at the N-terminal and hydrophobicity at the C-terminal are requisite for its histamine releasing activity. SP effectively released Ca2+ from the intracellular Ca store. The site of action of SP on the mast cell surface seems to be the same as that of compound 48/80. Eosinophil major basic protein (MBP) and histone are also effective for releasing histamine. The cDNA sequences of two subclasses of guinea pig MBP have been determined. These proteins may be released at the site of inflammation from the cells activated by the chemical mediators released from mast cells, and consequently, mast cell activation was reinforced. Such cell-to-cell interaction may be the reason for the augmentation of inflammation.
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PMID:[Recent advances in the research on histamine release]. 172 Jul 58

In order to better understand the neuroleptic-like effects of neurotensin in vivo, the effects of neurotensin in vitro on dopamine D2 and D1 agonist and antagonist binding sites were characterized in membranes from the neostriatum and the subcortical limbic area. Neurotensin increased the KD but not the Bmax value of S(-)[N-propyl-3H(N)]propylnorapomorphine [( 3H]NPA) binding sites with a maximal increase of 20-40% at 3-10 nM of neurotensin in both areas. The KD increase was preferentially due to an increase in the dissociation rate. The maximal reduction of [3H]NPA binding (35%) was obtained within 5 min from the addition of neurotensin. Neurotensin increased the KH of dopamine vs [3H]raclopride binding and, in the presence of GTP, also KL. Neurotensin did not affect the percentage of binding sites in the high vs low affinity states or the binding characteristics of [3H]spiperone, [3H]SKF 38393, and [3H]SCH 23390. Serotonin (10 nM), neuropeptide Y (10 nM), Substance P (10 nM), dynorphin A (10 nM), morphine (10 nM), nicotine (100 nM), gamma-amino-n-butyric acid (1 microM), or N-methyl-D-aspartate (1 microM) did not affect [3H]NPA binding. These results indicate that neurotensin in vitro selectively reduces D2 agonist affinity by an enhancement of the dissociation rate. This antagonistic intramembrane interaction may underlie the neuroleptic-like effects of neurotensin at low concentrations in vivo on D2 agonist binding, dopamine release, and on D2-mediated behaviours.
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PMID:Biochemical characterization of the intramembrane interaction between neurotensin and dopamine D2 receptors in the rat brain. 183 40

The binding of [3H]substance P (SP) to membranes of the rat small intestine demonstrates specific binding to receptors having more than one affinity for SP. The values of the binding parameters for the high-affinity site obtained from a non-linear regression analysis are as follows: KD = 0.25 nM, Bmax = 149.5 fmol/mg protein. Inhibition curves of 3H-SP binding using various unlabeled tachykinins show that the high-affinity receptor is of the P-subtype, having the highest affinity for SP and lower affinities for eledoisin and kassinin. Guanine nucleotides and sodium independently reduce the binding of 3H-SP to the high-affinity receptor in a dose-related manner; GTP and GDP are more potent than GMP. The reduction of specific SP binding by GTP can be ascribed primarily to an increase in the off-rate. The effects of guanine nucleotides on 3H-SP binding to membranes of rat small intestine suggest that the high-affinity receptor is linked to an effector by a GTP-binding regulatory protein.
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PMID:Guanine nucleotides regulate [3H]substance P binding in rat small intestine. 241 4

[3H]Substance P ([3H]SP) was used to characterize substance P (SP) receptor binding sites in guinea pig brain using membrane preparations and in vitro receptor autoradiography. Curvilinear Scatchard analysis shows that [3H]SP binds to a high affinity site (Kd = 0.5 nM) with a Bmax of 16.4 fmol/mg protein and a low affinity site (Kd = 29.6 nM) with a Bmax of 189.1 fmol/mg protein. Monovalent cations generally inhibit [3H]SP binding while divalent cations substantially increased it. The ligand selectivity pattern is generally similar to the one observed in rat brain membrane preparation with SP being more potent than SP fragments and other tachykinins. However, the potency of various nucleotides is different with GMP-PNP greater than GDP greater than GTP. The autoradiographic distribution of [3H]SP binding sites shows that high amounts of sites are present in the hippocampus, striatum, olfactory bulb, central nucleus of the amygdala, certain thalamic nuclei and superior colliculus. The cortex is moderately enriched in [3H]SP binding sites while the substantia nigra contains only very low amounts of sites. Thus, the autoradiographic distribution of SP binding sites is fairly similar in both rat and guinea pig brain.
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PMID:Pharmacological characterization and autoradiographic localization of substance P receptors in guinea pig brain. 243 87

The specific binding protein for substance P (SP) was solubilized in an active form from the crude mitochondrial (P2) fraction of bovine brainstem. After incubation with 3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate (CHAPS) and 0.1 M NaCl at 0 degrees C for 30 min, the SP binding to the supernatant fraction (100,000 g, 60 min) was determined by the glass fiber filtration method reported by Bruns et al. (1983). The specific [3H]SP binding to the solubilized fraction was highly specific for SP and was displaced by nanomolar concentrations of SP and physalaemin, but only by micromolar concentrations of eledoisin. In addition, the binding was inhibited by GTP (approximately 40% of the specific binding decreased by 10 microM GTP) in both preparations. These results were virtually identical to those of P2 membrane preparations and suggested that this high-affinity SP binding site belongs to the SP-P type. Scatchard analyses of SP binding to the solubilized fraction revealed a single saturable component with a Bmax of 22.0 +/- 5.10 fmol/mg protein and a KD of 0.79 nM, and these values are almost the same as those obtained in the P2 fraction (Bmax = 31.3 +/- 3.56 fmol/mg protein, KD = 0.82 nM). Gel filtration analysis showed that the detergent-SP binding protein complex has two calculated molecular weights of greater than 1,000,000 and 55,000-60,000 (a corresponding Stokes radius of 35.5 nm).
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PMID:Solubilization and characterization of substance P binding protein from bovine brainstem. 244 42

Substance P excites neurons by suppressing inward rectification channels. We have investigated whether the substance P receptor interacts with the inward rectification channels through a guanine nucleotide-binding protein (G protein) by using dissociated cultured neurons from the nucleus basalis of newborn rats. During intracellular application of guanosine 5'-[gamma-thio]triphosphate and 5'-guanylyl imidodiphosphate, hydrolysis-resistant GTP analogues that irreversibly stimulate G proteins, substance P application almost irreversibly suppressed the inward rectification channels. Pretreatment with pertussis toxin did not significantly influence substance P action. Intracellular application of cAMP and 3-isobutyl-1-methylxanthine or of 9-(tetrahydro-2-furyl)adenine (SQ 22,536), an inhibitor of adenylate cyclase, did not alter the substance P-induced response. We conclude that the inhibition of inward rectification channels by substance P is mediated through a G protein. However, the effect is not mediated through adenylate cyclase or the cAMP system. This G protein, which is insensitive to pertussis toxin, could be an unidentified G protein.
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PMID:Pertussis toxin-insensitive G protein mediates substance P-induced inhibition of potassium channels in brain neurons. 245 66

Regulation of neuronal calcium channels by GTP-binding proteins (G proteins) is likely to be an important mechanism by which inhibitory transmitters influence excitation-secretion coupling in presynaptic nerve endings. Here, we report that in peripheral sensory neurons from embryonic chick dorsal root ganglia (DRG), the G protein-mediated inhibition of voltage-dependent calcium channels may best explain how norepinephrine (NE) and GABA inhibit the electrically evoked, calcium-dependent release of substance P (SP). As is the case for the previously reported inhibitory actions of these transmitters on DRG cell calcium channels, we demonstrate that NE and GABA inhibit peptide secretion through activation of alpha-adrenergic and GABAb receptors that are functionally coupled to pertussis toxin (PTX)-sensitive G proteins. Pretreatment of DRG cell cultures with PTX blocked the ability of NE and GABA to inhibit the release of SP, an action correlated with PTX-catalyzed ADP-ribosylation of membrane proteins with apparent molecular weight (Mr) of 40-41 kDa. Western immunoblot analysis of chick DRG cell membrane proteins using antisera directed against synthetic peptides corresponding to amino acid sequences predicted from cDNAs for PTX-sensitive G protein alpha subunits revealed a minimum of 2 Gi-like proteins (Mr 40 and 41 kDa) and a third Go-like protein (Mr 40 kD). Significantly, these findings implicate Gi- and/or Go-like GTP-binding proteins as mediators of presynaptic inhibition in peripheral sensory neurons.
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PMID:G proteins couple alpha-adrenergic and GABAb receptors to inhibition of peptide secretion from peripheral sensory neurons. 246 94

Mg2+ increased but Na+ and GTP decrease [3H]substance P (SP) binding to rat cerebral cortical membranes and to 10 mM 3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate (CHAPS)-solubilized membrane fraction. To determine the binding parameters that are modified by the cations and GTP, inhibition experiments of [3H]SP binding by unlabeled SP were performed in both of the preparations. Nonlinear least-squares regression analysis of data in the membrane fraction indicated that optimal fitting of the inhibition curves in the presence of 10 mM MgCl2 was attained with a two-site model, corresponding to a "high-affinity (H)" and a "low-affinity (L)" state. By omitting MgCl2, or by addition of NaCl and GTP, the [3H]SP specific binding was decreased, the H state disappeared, and the L state and a new "super-low affinity (SL)" state observed. The SP/[3H]SP inhibition curves in the cerebral cortical membranes by in vivo treatment with pertussis toxin (islet-activating protein) were similar to that in the presence of GTP in control membranes. The effects of MgCl2, NaCl, and GTP were greater in the CHAPS-solubilized fraction than in the membrane fraction. In contrast to the membrane fraction, the inhibition curves of [3H]SP binding by unlabeled SP in the presence of MgCl2 in the CHAPS-solubilized fraction were best fitted to a one-site model. The KD value was relatively close to that of the low-affinity state in the membrane fraction. Even with the addition of NaCl or GTP, or by reducing MgCl2 concentration to 1 mM, although the inhibition curves consistently fit the one-site model, the KD values changed only slightly.
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PMID:Comparison of the effects of ions and GTP on substance P binding to membrane-bound and solubilized specific sites. 247 98

Modulation of the voltage-gated K+ conductance in T-lymphocytes by substance P was examined. Whole-cell recordings from JurkaT E6-1 human T-lymphocytes revealed two components of substance P action on the outward K+ current: (i) dose- and time-dependent reduction of current peak amplitude; and (ii) acceleration of the current inactivation rate. This action was blocked by substituting Cs+ for K+ in the recording pipette and by the substance P antagonist. [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P. As indicated by conductance-voltage relationship, the reduction in current peak amplitude as a result of substance P application was not due to a shift of the voltage dependence of the channel. Raising intracellular free calcium concentration from 2 to 200 nM reversed the reduction, induced by substance P, in current peak amplitude and disclosed an apparent desensitization towards the neuropeptide action. The treatment, however, did not reverse substance P-induced acceleration of the rate of current decay. Intracellular administration of hydrolysis-resistant guanosine triphosphate (to persistently activate GTP-binding protein) and guanosine diphosphate (to competitively inhibit GTP-binding proteins) analogues mimicked and inhibited substance P-induced reduction of K+ conductance, respectively. The data demonstrate a modulation of T-lymphocyte K+ channels by substance P and substantiate a possible role for GTP-binding proteins in this modulation.
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PMID:Modulation of membrane K+ conductance in T-lymphocytes by substance P via a GTP-binding protein. 248 61


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