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

To investigate substance P (SP) receptors on an established human astrocytoma cell line (U-87 MG), [3H][Sar9,Met(O2)11]-SP, a selective SP receptor agonist, was used to identify and characterize the cell membrane binding sites for SP. SP receptor mRNA was examined by solution hybridization analysis, and the existence of SP binding protein on the surface of membranes was evaluated by flow cytometry using an anti-SP binding protein antibody. In U-87 MG and U-373 MG RNA preparations, transcripts were identified that corresponded to both mature and partially spliced receptor forms. In U-87 MG cell membrane-enriched preparations, the binding of [3H][Sar9,Met(O2)11]-SP was found to be time and cell number dependent, specific, saturable, and of high affinity. Equilibrium binding analysis revealed a single class of binding sites with an apparent KD of 1.15 +/- 0.15 nM and a Bmax of 108 +/- 9.8 fmol/mg of protein. [3H][Sar9, Met(O2)11]-SP binding was basically not influenced by addition of mono (Na+, Li+) or divalent (Mg2+, Mn2+, Ca2+) cations; only high doses of divalent cations decreased the binding. GTP and guanylyl-5'-imidodiphosphate, but not GDP and GMP, reduced the Bmax without changing the affinity of [3H][Sar9,Met(O2)11]-SP. We also examined the effects of pretreatment with three lectins [concanavalin A (con A), wheat germ agglutinin (WGA), and Lens culinaris agglutinin (LCA)] to determine the nature of carbohydrate chains on the U-87 MG cell. Of three lectins analyzed for effects on agonist binding, WGA and LCA had an inhibitory effect, whereas con A was ineffective. These results suggest that SP receptors on the human astrocytoma cell line U-87 MG have either a biantennary complex-type or a high mannose-type of carbohydrate chain and may be regulated by GTP-binding protein(s).
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PMID:Human astrocytoma cells (U-87 MG) exhibit a specific substance P binding site with the characteristics of an NK-1 receptor. 886 85

1. Radioimmunological techniques were used in isolated guinea-pig inferior mesenteric ganglion (IMG)-colon preparations to determine whether opioid peptides and neurotensin8-13 (NT8-13), the C-terminal region of NT1-13 recognized by neurotensin receptors, modulate distension-induced release of substance P (SP)- and vasoactive intestinal polypeptide (VIP)-like immunoreactive (LI) material. 2. Colonic distension significantly increased the amount of SP- and VIP-LI material released in the ganglionic superfusate. A low-Ca2+ (0.1 mM), high-Mg2+ (15 mM) solution blocked their release. 3. In vivo capsaicin pretreatment abolished release of SP-LI material during colonic distension but had no significant effect on distension-induced release of VIP-LI material. 4. The addition of [Leu5]enkephalin, [Met5]enkephalin, PL017 (a mu-receptor agonist) and DPDPE (a delta-receptor agonist) to the ganglion side of a two-compartment chamber blocked distension-induced release of SP-LI material. The addition of naloxone and ICI-174,864 (a delta-receptor antagonist) to the ganglion compartment reversed the inhibitory effect of the mu- and delta-receptor agonists. 5. Addition of [Leu5]enkephalin and [Met5]enkephalin to the ganglion compartment had no significant effect on release of VIP-LI material during colonic distension. 6. Addition of NT8-13 to the ganglion compartment significantly increased in the amount of SP-LI material released during colonic distension but had no affect on distension-induced release of VIP-LI material. 7. The results suggest the hypothesis that under in vivo conditions, enkephalinergic nerves decrease and neurotensinergic nerves increase the release of SP from peripheral branches of primary afferent sensory nerves.
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PMID:Modulation by opioid peptides of mechanosensory pathways supplying the guinea-pig inferior mesenteric ganglion. 886 66

1. The role of NK1 and NK3 receptors in synaptic transmission between myenteric neurons during motility reflexes in the guinea-pig ileum was investigated by recording intracellularly the reflex responses of the circular muscle to distension or compression of the mucosal villi. Experiments were performed in a three-chambered organ bath that enabled drugs to be selectively applied to different sites along the reflex pathways. 2. When applied in the recording chamber, an NK1 receptor antagonist, SR140333 (100 nM), reduced by 40-50% the amplitudes of inhibitory junction potentials (i.j.ps) evoked in the circular muscle by activation of descending reflex pathways. This effect was abolished when synaptic transmission in the stimulus region was blocked with physiological saline containing 0.1 mM Ca2+ plus 10 mM Mg2+, leaving only the component of the descending reflex pathway conducted via long anally directed collaterals of intrinsic sensory neurons. 3. SR140333 (100 nM) had no effect on descending reflex i.j.ps when applied to the stimulus region. Ascending reflexes were also unaffected by SR140333 in the stimulus region or between the stimulus and recording sites. 4. Septide (10 nM), an NK1 receptor agonist, enhanced descending reflexes by 30-60% when in the recording chamber. [Sar9,Met(O2)11]substance P had no effect at 10 nM, but potentiated distension-evoked reflexes at 100 nM. 5. A selective NK3 receptor antagonist, SR142801 (100 nM), when applied to the stimulus region, reduced the amplitude of descending reflex responses to compression by 40%, but had no effect on responses to distension. SR142801 (100 nM) had no effect when applied to other regions of the descending reflex pathways. 6. SR142801 (100 nM) only inhibited ascending reflexes when applied at the recording site. However, after nicotinic transmission in the stimulus region was blocked, SR142801 (100 nM) at this site reduced responses to compression. 7. Contractions of the circular muscle of isolated rings of ileum evoked by low concentrations of septide, but not [Sar9,Met(O2)11]substance P, were potentiated by tetrodotoxin (300 nM). 8. Contractile responses evoked by an NK3 receptor agonist, senktide, were non-competitively inhibited by SR142801. After excitatory neuromuscular transmission was blocked, senktide produced inhibitory responses that were also antagonised by SR142801, but to a lesser extent and in an apparently competitive manner. 9. These results indicate that tachykinins acting via NK1 receptors partly mediate transmission to inhibitory motor neurons. NK3 receptors play a role in transmission from intrinsic sensory neurons and from ascending interneurons to excitatory motor neurons during motility reflexes.
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PMID:Roles of neuronal NK1 and NK3 receptors in synaptic transmission during motility reflexes in the guinea-pig ileum. 972 48

Conventional intracellular recordings were made from 26 lateral spinal nucleus (LSN) neurons in slices of L6-S1 spinal cord from 10- to 15-day-old rats. At rest, LSN neurons did not fire spontaneous action potentials. With injection of a positive current pulse, action potentials had an amplitude of 72 +/- 7 (SD) mV and duration at half-peak height of 0.75 +/- 0.22 ms. Action potentials were followed by an afterpotential. Most LSN neurons (13/17) exhibited only an afterhyperpolarization (AHP); four neurons exhibited both a fast and a slow AHP separated by an afterdepolarization (ADP). For LSN neurons that exhibited only an AHP, a slow ADP could be identified during bath application of apamin (100 nM). Four of 11 LSN neurons showed a postinhibitory rebound (PIR). Two types of PIR were noted, one with high threshold and low amplitude and the other with low threshold and high amplitude. The PIR with high amplitude was partially blocked in 0 mM Ca2+/high Mg2+ (10 mM) recording solution. Repetitive firing properties were examined in 17 LSN neurons. On the basis of the ratio of the slopes between initial instantaneous firing and steady-state firing frequencies, neurons with low spike frequency adaptation (SFA, 8/17) and high SFA (4/17) were identified. In addition, 2/17 LSN neurons exhibited biphasic repetitive firing patterns, which were composed of a fast SFA, delayed excitation, and low SFA; another two neurons showed only delayed excitation. Plateau potentials also were found in two LSN neurons. Dorsal root stimulation revealed that most LSN neurons (12/13) had polysynaptic postsynaptic potentials (PSP); only one neuron exhibited a monosynaptic PSP. Electrical stimulation of the dorsal root evoked prolonged discharges in low SFA neurons and a short discharge in high SFA neurons. Intrinsic properties were modulated by bath application of substance P (SP). Membrane potentials were depolarized in all eight LSN neurons tested, and membrane resistance was either increased (n = 3) or decreased (n = 2). Both instantaneous firing and steady-state firing were facilitated by SP. In addition, oscillation of membrane potentials were induced in three LSN neurons. These results demonstrate that LSN neurons exhibit a variety of intrinsic properties, which may significantly contribute to sensory processing, including nociceptive processing.
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PMID:Cellular properties of lateral spinal nucleus neurons in the rat L6-S1 spinal cord. 1036 22

1. Although a number of interventional pharmacotherapies have undergone clinical trial in traumatic brain injury (TBI), none has shown considerable promise. The present short review will examine some of the more novel compounds that have been proposed recently as potential therapeutic agents for use in TBI. 2. Previous experimental studies have demonstrated that brain intracellular free magnesium significantly declines following TBI and that the administration of magnesium salts attenuates the post-traumatic neurological deficits. More recent studies have established that magnesium salts administered after trauma enter the brain intracellular space and reduce the size of the lesion volume. Such protection could be afforded through attenuation of both necrotic and apoptotic cell death. Magnesium salts are currently on clinical trial in TBI. 3. Cyclosporine A is known to inhibit opening of the mitochondrial permeability transition pore. Administration of cyclosporine A after TBI has been shown to attenuate axonal injury and decrease the resultant lesion volume. Therefore, inhibitors of mitochondrial transition pore opening and resultant attenuation of apoptosis show some promise as neuroprotective agents. 4. Recent evidence has shown that substance P antagonists may decrease lesion volume and improve neurological outcome after ischaemia. Similar findings have recently been reported in TBI. The fact that substance P antagonists are known to reduce neurogenic inflammation, oedema formation and are clinically being trialed as both antidepressants and antinociceptive agents suggests that these agents warrant further investigation as therapeutic agents following TBI. 5. There are numerous contradictions in the literature regarding the potential neuroprotective effects of the hormones oestrogen and progesterone. Recent studies suggest that both hormones are protective in TBI and further studies are required to ascertain the mechanisms associated with this protection and any potential for clinical application.
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PMID:An overview of new and novel pharmacotherapies for use in traumatic brain injury. 1170 96

1. Magnesium (Mg)-deficient rats develop a mechanical hyperalgesia which is reversed by a N-Methyl-D-Aspartate (NMDA) receptor antagonist. Given that functioning of this receptor-channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in turn trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non-NMDA receptors as well as compounds interfering with the functioning of intracellular second messengers for effects on hyperalgesia in Mg-deficient rats. 2. Hyperalgesic Mg-deficient rats were administered intrathecally (10 microl) or intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in response to a mechanical stimulus (paw pressure test) over 2 h. 3. Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 micromol) as well as NMDA receptor antagonists such as MK-801 (0.6, 6.0, 60 nmol), AP-5 (10.2, 40.6, 162.3 nmol) and DCKA (0.97, 9.7, 97 nmol) dose-dependently reversed the hyperalgesia. Chelerythrine chloride, a protein kinase C (PKC) inhibitor (1, 10.4, 104.2 nmol) and 7-NI, a specific nitric oxide (NO) synthase inhibitor (37.5, 75, 150 micromol x kg(-1), i.p.) induced an anti-hyperalgesic effect in a dose-dependent manner. SR-140333 (0.15, 1.5, 15 nmol) and SR-48968 (0.17, 1.7, 17 nmol), antagonists of neurokinin receptors, produced a significant, but moderate, increase in vocalization threshold. 4. These results demonstrate that Mg-deficiency induces a sensitization of nociceptive pathways in the spinal cord which involves NMDA and non-NMDA receptors. Furthermore, the data is consistent with an active role of PKC, NO and, to a lesser extent substance P in the intracellular mechanisms leading to hyperalgesia.
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PMID:Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats. 1170 42

A previously unknown genetic defect in magnesium metabolism (i.e., the magnesium-binding defect [MgBD]) was found to be associated with the cause of "salt-sensitive" essential hypertension in humans and rats. It inhibits the entrance of Mg2+ into the cell so that the intracellular concentrations of Mg2+ and MgATP2- are decreased. Consequently, the 300 enzyme reactions in the cell, especially the 100 that either use or produce MgATP2-, are inhibited. Thus, because the extrusion of intracellular Na+ requires MgATP2-, hypertension results when the involved MgATP2- requiring enzyme is inhibited. The MgBD is corrected by the tachykinin substance P, which occurs in normal blood plasma, and by the pentapeptide and its contained tetrapeptide, which are released from the C-terminal region of substance P by plasma aminopeptidases. In vivo, the intravenous administration of the tetrapeptide corrects the hypertension and the MgBD as well. The MgBD also occurs in type 2 diabetes mellitus and, thus, the decreased intracellular concentrations of Mg2+ and MgATP2- ions appear to be involved also in the cause of this disease, which is reputed to be the fifth most deadly disease in the world.
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PMID:Abnormal magnesium metabolism in etiology of salt-sensitive hypertension and type 2 diabetes mellitus. 1507 8

We examined specific receptor/transmitter combinations used at functionally identified synapses in ascending and descending reflex pathways of guinea pig distal colon. Excitatory (EJPs) or inhibitory junction potentials (IJPs) were recorded intracellularly from nicardipine-paralyzed circular smooth muscle in either the oral or anal recording chamber of a three-chambered organ bath, respectively. Blockade of synaptic transmission in the central chamber with a 0.25 mM Ca2+/12 mM Mg2+ solution abolished EJPs evoked by distension applied either in the central or the far (anal) chamber. IJPs evoked by distension in the central or the far (oral) chamber were depressed to approximately 50% of control. Hexamethonium (nicotinic receptor antagonist, 200 microM) in the central chamber reduced IJPs evoked by far or central distension to 50%, whereas EJPs evoked by far distension were abolished and EJPs evoked by central distension were reduced to 70% of control. Hexamethonium in the recording chambers reduced both IJPs and EJPs evoked by central distension to approximately 50%. EJPs in the ascending pathway were unaffected by blockade of muscarinic receptors in the central chamber or blockade of neurokinin 3 tachykinin receptors in this or the recording chamber. In the descending pathway, blockade of P2 receptors in the same chambers had only a minor effect on distension-evoked IJPs. Thus some intrinsic sensory neurons of guinea pig colon have long descending projections (>30 mm), but ascending projections of <15 mm. In contrast to the ileum, transmission between ascending or descending interneurons and from sensory neurons to descending interneurons is predominantly via nicotinic receptors; but transmission to inhibitory or excitatory motoneurons and from sensory neurons to ascending interneurons involves nicotinic and other unidentified receptors.
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PMID:Synaptic transmission in simple motility reflex pathways excited by distension in guinea pig distal colon. 1525 59

Magnesium is a micronutrient essential for the normal functioning of the cardiovascular system, and Mg deficiency (MgD) is frequently associated in the clinical setting with chronic pathologies such as CHF, diabetes, hypertension, and other pathologies. Animal models of MgD have demonstrated a systemic pro-inflammatory/pro-oxidant state, involving multiple tissues/organs including neuronal, hematopoietic, cardiovascular, and gastrointestinal systems; during later stages of MgD, a cardiomyopathy develops which may result from a cascade of inflammatory events. In rodent models of dietary MgD, a significant rise in circulating levels of proinflammatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide among others, was observed within days (1-7) of initiating the Mg-restricted diet, and implicated a neurogenic trigger for the subsequent inflammatory events; this early "neurogenic inflammation" phase may be mediated in part, by the Mg-gated N: -methyl-D-aspartate (NMDA) receptor/channel complex. Deregulation of the NMDA receptor may trigger the abrupt release of neuronal SP from the sensory-motor C-fibers to promote the subsequent pro-inflammatory changes: elevations in circulating inflammatory cells, inflammatory cytokines, histamine, and PGE(2) levels, as well as formation of nitric oxide, reactive oxygen species, lipid peroxidation products, and depletion of key endogenous antioxidants. Concurrent elevations of tissue CD14, a high affinity receptor for lipopolyssacharide, suggest that intestinal permeability may be compromised leading to endotoxemia. If exposure to these early (1-3 weeks MgD) inflammatory/pro-oxidant events becomes prolonged, this might lead to impaired cardiac function, and when co-existing with other pathologies, may enhance the risk of developing chronic heart failure.
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PMID:The nerve-heart connection in the pro-oxidant response to Mg-deficiency. 1681 76

Electron capture dissociation (ECD) of the peptide Substance P (SubP) complexed with divalent metals has been investigated. ECD of [SubP + H + M]3+ (M2+ = Mg2+ -Ba2+ and Mn2+ -Zn2+) allowed observation of a larger number of product ions than previous investigations of doubly charged metal-containing peptides. ECD of Mg-Ba, Mn, Fe, and Zn-containing complexes resulted in product ions with and without the metal from cleavage of backbone amine bonds (c' and z* -type ions). By contrast, ECD of Co and Ni-containing complexes yielded major bond cleavages within the C-terminal methionine residue (likely to be the metal ion binding site). Cu-containing complexes displayed yet another behavior: amide bond cleavage (b and y'-type ions). We believe some results can be rationalized both within the hot hydrogen atom mechanism and mechanisms involving electron capture into excited states, such as the recently proposed amide superbase mechanism. However, some behavior, including formation of (cn 'M - H)+ ions for Ca-Ba, is best explained within the latter mechanisms with initial electron capture at the metal. In addition, the ECD behavior appears to correlate with the metal second ionization energy (IE2). Co and Ni (displaying sequestered fragmentation) have IE2s of 17.1 and 18.2 eV, respectively, whereas IE2s for Mg-Ba, Mn, and Fe (yielding random cleavage) are 10.0 to 16.2 eV. This behavior is difficult to explain within the hot hydrogen atom mechanism because hydrogen transfer should not be influenced by IE2s. However, the drastically different fragmentation patterns for Co, Ni, and Cu compared to the other metals can also be explained by their higher propensity for nitrogen (as opposed to oxygen) binding. Nevertheless, these results imply that directed fragmentation can be accomplished via careful selection of the cationizing agent.
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PMID:Divalent metal ion-peptide interactions probed by electron capture dissociation of trications. 1695 59


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