Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We examined the tail-flick response to various heat intensities in diabetic and non-diabetic mice. Heat intensities were set to one of five values by adjusting the source voltage of a 50-W projection bulb to 25, 35, 50, 65 and 80 V. These heat intensities produced surface skin heating rates of 0.1, 0.4, 0.9, 3.0 and 7.3 degrees C/s, respectively. Tail-flick latencies at source voltages of 35 and 50 V in diabetic mice were significantly shorter than those in non-diabetic mice. However, there were no significant differences in tail-flick latencies at 25, 65 and 80 V. In non-diabetic mice, tail-flick latencies were not affected by intrathecal (i.t.) pretreatment with capsaicin 24 h before testing. Tail-flick latencies at 35 and 50 V in diabetic mice were increased by pretreatment with capsaicin. Moreover, although tail-flick latencies in non-diabetic mice were not affected by i.t. pretreatment with calphostin C, a selective protein kinase C inhibitor, those at 35 and 50 V in diabetic mice were increased. However, i.t. pretreatment with (8R, 9S, 11S)-(-)-9-hydroxy-9-n-hexyloxy-carbonyl-8-methyl-2, 3, 9, 10-tetrahydro-8, 11-epoxy-1H, 8H, 11H-2, 7b, 11a-triazadibenzo [a, g]cycloocta[cde]-trinden-1-one (KT5720), a selective protein kinase A inhibitor, did not affect tail-flick latencies in either diabetic or non-diabetic mice. In non-diabetic mice, i.t. pretreatment with phorbol 12,13-dibutyrate (PDB), a protein kinase C activator, decreased tail-flick latencies at 35 and 50 V. Tail-flick latencies in diabetic mice were not affected by i.t. pretreatment with PDB 60 min before testing. Furthermore, the attenuation of tail-flick latencies induced by i.t. pretreatment with PDB in non-diabetic mice was reversed by i.t. pretreatment with capsaicin 24 h before testing. These results indicate that diabetic mice exhibit thermal allodynia and hyperalgesia. Furthermore, this thermal allodynia and hyperalgesia in diabetic mice may be due to the enhanced release of substance P followed by activation of protein kinase C in the spinal cord.
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PMID:Possible involvement of spinal protein kinase C in thermal allodynia and hyperalgesia in diabetic mice. 1039 15

A rat kidney epithelial cell line expressing the rat neurokinin-1 receptor (NK-1 R) was used to investigate the relationship between receptor phosphorylation and desensitization. Substance P (SP) maximally stimulated cellular inositol 1,4,5-trisphosphate (IP3) production 14-fold within 3 s, after which cellular IP3 levels rapidly diminished to near basal levels in the continuing presence of SP. SP also caused concentration-dependent phosphorylation of the NK-1R, and this effect was blocked by a receptor antagonist. Stimulation with 100 nM SP for as little as 2 s resulted in 90% desensitization of the receptor to restimulation by SP, and near-maximal receptor phosphorylation was observed at 5 s. Receptor desensitization was not affected by agents that affect protein kinase A. Phorbol 12-myristate 13-acetate (PMA) also caused phosphorylation and desensitization of the receptor but with slower kinetics and to a lesser extent than SP. PMA- but not SP-induced NK-1 R desensitization and phosphorylation were abolished by the protein kinase C inhibitor bisindolylmaleimide 1. The concentration-response curves for SP-stimulated IP3 signaling and desensitization were similar, but the curve for NK-1R phosphorylation was shifted to the right and was steeper, suggesting that the relationship between desensitization and phosphorylation is complex. These results show that both rapid homologous and rapid heterologous NK-1R desensitizations may be mediated by receptor phosphorylation but occur via distinct mechanisms with different kinetics and efficacies.
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PMID:Phosphorylation and desensitization of neurokinin-1 receptor expressed in epithelial cells. 1053 50

The effects of substance P (SP) on nicotinic acetylcholine (ACh)-evoked currents were investigated in parasympathetic neurons dissociated from neonatal rat intracardiac ganglia using standard whole cell, perforated patch, and outside-out recording configurations of the patch-clamp technique. Focal application of SP onto the soma reversibly decreased the peak amplitude of the ACh-evoked current with half-maximal inhibition occurring at 45 microM and complete block at 300 microM SP. Whole cell current-voltage (I-V) relationships obtained in the absence and presence of SP indicate that the block of ACh-evoked currents by SP is voltage independent. The rate of decay of ACh-evoked currents was increased sixfold in the presence of SP (100 microM), suggesting that SP may increase the rate of receptor desensitization. SP-induced inhibition of ACh-evoked currents was observed following cell dialysis and in the presence of either 1 mM 8-Br-cAMP, a membrane-permeant cAMP analogue, 5 microM H-7, a protein kinase C inhibitor, or 2 mM intracellular AMP-PNP, a nonhydrolyzable ATP analogue. These data suggest that a diffusible cytosolic second messenger is unlikely to mediate SP inhibition of neuronal nicotinic ACh receptor (nAChR) channels. Activation of nAChR channels in outside-out membrane patches by either ACh (3 microM) or cytisine (3 microM) indicates the presence of at least three distinct conductances (20, 35, and 47 pS) in rat intracardiac neurons. In the presence of 3 microM SP, the large conductance nAChR channels are preferentially inhibited. The open probabilities of the large conductance classes activated by either ACh or cytisine were reversibly decreased by 10- to 30-fold in the presence of SP. The single-channel conductances were unchanged, and mean apparent channel open times for the large conductance nAChR channels only were slightly decreased by SP. Given that individual parasympathetic neurons of rat intracardiac ganglia express a heterogeneous population of nAChR subunits represented by the different conductance levels, SP appears to preferentially inhibit those combinations of nAChR subunits that form the large conductance nAChR channels. Since ACh is the principal neurotransmitter of extrinsic (vagal) innervation of the mammalian heart, SP may play an important role in modulating autonomic control of the heart.
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PMID:Substance P preferentially inhibits large conductance nicotinic ACh receptor channels in rat intracardiac ganglion neurons. 1102 89

Angiotensin II (Ang II) plays an important role in the central control of blood pressure and baroreflexes. These effects are initiated by stimulation of Ang II type 1 (AT(1)) receptors on neurons within the hypothalamus and brain stem, and involve increasing the activity of noradrenergic, substance P, and glutamatergic pathways. The goal of this study is to investigate the intracellular signaling molecules, which are involved in mediating the Ang II-induced increases in neuronal activity. Using neurons in primary culture from newborn rat hypothalamus and brain stem, we have previously determined that Ang II elicits an AT(1) receptor-mediated inhibition of delayed rectifier K(+) current, a stimulation of Ca(2+) current, and a consequent increase in firing rate. In the present study we have demonstrated that this chronotropic action of Ang II in neuronal cultures involves activation of Ca(2+)-dependent signaling molecules. The Ang II-induced increase in firing rate was abolished by inhibition of phospholipase C with U73122 (10 micromol/L), and was attenuated by the protein kinase C inhibitor calphostin C (10 micromol/L) or by the calcium/calmodulin-dependent kinase II (CaMKII) inhibitor KN-93 (10 micromol/L). A combination of calphostin C and KN-93 completely inhibited this Ang II action. These results indicate that the AT(1) receptor-mediated increase in neuronal firing rate involves activation of both PKC and CaMKII, and suggest that these enzymes are potential targets for manipulating the central actions of Ang II.
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PMID:Chronotropic action of angiotensin II in neurons via protein kinase C and CaMKII. 1188 8

The present study examined the levels of NMDA receptor NR2 subunit tyrosine phosphorylation in a rat model of inflammation and correlated it with the development of inflammation and hyperalgesia. Hindpaw inflammation and hyperalgesia were induced by intraplantar injection of complete Freund's adjuvant. Proteins from the spinal cord (L4-L5) were immunoprecipitated with anti-NR2A or anti-NR2B antibodies and used for subsequent analysis using 4G-10, a specific anti-phosphotyrosine antibody. Compared with naive rats, there was a rapid and prolonged increase in tyrosine phosphorylation of the NR2B, but not NR2A, subunit after inflammation. The increase in NR2B tyrosine phosphorylation was dependent on primary afferent drive because (1) the phosphorylation correlated with the temporal profile of inflammation and hyperalgesia, (2) shorter-duration noxious stimulation produced a rapid and shorter-lasting increase in phosphorylation, and (3) local anesthetic block of the injected paw reversibly blocked inflammation-induced NR2B tyrosine phosphorylation and delayed hyperalgesia. The increase in NR2B tyrosine phosphorylation was abolished by intrathecal pretreatment with genistein, a tyrosine kinase inhibitor; PP2, an Src family tyrosine kinase inhibitor; AIDA, a group I metabotropic glutamate receptor antagonist; L733,060, an NK1 tachykinin receptor antagonist, and chelerythrine, a protein kinase C inhibitor. In addition, intrathecal PP2 delayed the onset of mechanical hyperalgesia and allodynia. These findings correlate in vivo NMDA receptor tyrosine phosphorylation with the development and maintenance of inflammatory hyperalgesia and suggest that signal transduction upstream to NR2B tyrosine phosphorylation involves G-protein-coupled receptors and PKC and Src family protein tyrosine kinases.
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PMID:Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord during the development and maintenance of inflammatory hyperalgesia. 1212 79

Whole cell patch-clamp techniques were used to examine neurokinin receptor modulation of Ca2+ channels in small to medium size dorsal root ganglia neurons (<40 pF) that express mainly N- and L-type Ca2+ currents. Low concentrations of substance P enhanced Ca2+ currents (5-40%, <0.2 microM), while higher concentrations applied cumulatively reversed these enhancements (5-28% reductions, >0.5 microM). This apparent inhibition by high concentrations of substance P was blocked by the administration of the NK3 antagonist SB 235,375 (0.2 microM). The NK1 agonist, [Sar9,Met11]-substance P (0.05 to 1.0 microM) did not alter Ca2+ currents; whereas the NK2 agonist, [betaAla8]-neurokinin A (4-10), enhanced Ca2+ currents (5-36% increase, 0.05-0.5 microM). The enhancement was reversed by the NK2 antagonist MEN 10,376 (0.2 microM) but unaffected by the NK3 antagonist SB 235,375 (0.2 microM). The NK3 agonist [MePhe7]-neurokinin B (0.5-1.0 microM) inhibited Ca2+ currents (6-24% decrease). This inhibition was not prevented by the NK2 antagonist MEN 10,376 (0.2 microM) but was blocked by the NK3 antagonist SB 235,375 (0.2 microM). Both the enhancement and inhibition of Ca2+ currents by neurokinin agonists were reversed by the protein kinase C inhibitor bisindolylmaleimide I HCl (0.2-0.5 microM). Following inhibition of Ca2+ channels by [MePhe7]-neurokinin the facilitatory effect of BayK 8644 (5 microM) was increased and the inhibitory effect of the N-type Ca2+ channel blocker w -conotoxin GVIA (1 microM) was diminished, suggesting that the NK3 agonist inhibits N-type Ca2+ channels. Similarly, block of all but N-type Ca2+ channels, revealed that [betaAla8]-neurokinin A (4-10) enhanced the currents while [MePhe7]-neurokinin B inhibited the currents. Inhibition of all but L-type Ca2+ channels, revealed that [betaAla8]-neurokinin A (4-10) enhanced the currents while [MePhe7]-neurokinin B had no effect. Activation of protein kinase C with low concentrations of phorbol-12,13-dibutyrate enhanced Ca2+ currents, but high concentrations inhibited N- and L-type Ca2+ currents. In summary, these data suggest that in adult rat dorsal root ganglia neurons, NK2 receptors enhance both L- and N-type Ca2+ channels and NK3 receptors inhibit N-type Ca2+ channels and that these effects are mediated by protein kinase C phosphorylation of Ca2+ channels.
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PMID:Protein kinase C is involved in neurokinin receptor modulation of N- and L-type Ca2+ channels in DRG neurons of the adult rat. 1266 Mar 48

Mast cells play a central role in immediate type hypersensitivity and inflammatory events. Activation of mast cells not only can result in the release of preformed granule-associated mediators generally followed by de novo synthesis of lipid-derived substances. In the present study, we show that mast cell can be activated to release lipid mediators in absence of granule exocytosis. Primary cultured murine mast cells were stimulated with substance P and produced leukotriene C4, and prostaglandin D2 without the release of the granule-associated enzyme beta-hexosaminidase. Indomethacin and nordihydroguaiaretic acid caused complete inhibition of arachidonic metabolite generation. Leukotriene C4 and prostaglandin D2 production was blocked by genistein, a specific inhibitor of tyrosine kinases, and bisindolylmaleimide, a protein kinase C inhibitor, indicating a role for both phosphorylation pathways in the substance P-stimulated lipid mediator production. We suggest that the cytokine microenvironment of the mast cell determines whether mast cell stimulation leads to only lipid mediator release or full activation. Analysis of granule-associated mediators only might underestimate the role of mast cell activation under (patho)physiological conditions.
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PMID:Substance P can stimulate prostaglandin D2 and leukotriene C4 generation without granule exocytosis in murine mast cells. 1506 54

We have shown that neurokinin A-induced contraction of human sigmoid circular muscle (HSCM) is reduced in patients with ulcerative colitis and that interleukin (IL)-1beta may play a role in this change. We now examine changes in the signal transduction pathway mediating neurokinin A-induced contraction of HSCM and explore the role of IL-1beta and of H(2)O(2) in these changes. In Fura 2-AM-loaded ulcerative colitis HSCM cells, neurokinin A- and caffeine-induced peak Ca(2+) increase and cell shortening were significantly reduced. In normal cells, neurokinin A-induced contraction was decreased by protein kinase C inhibitor chelerythrine and by calmodulin inhibitor CGS9343B [1,3-dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one (1:1) maleate]. In ulcerative colitis muscle cells, contraction was inhibited only by chelerythrine but not by CGS9343B. IL-1beta treatment of normal HSCM strips and cells reproduced the changes observed in ulcerative colitis. IL-1beta-induced reduction in caffeine-induced peak Ca(2+) increase and contraction was reversed by catalase, suggesting a role of H(2)O(2). IL-1beta-induced H(2)O(2) production was inhibited by mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059 (2'-amino-3'-methoxyflavone) and by cytosolic phospholipase A2 (cPLA(2)) inhibitor AACOCF3 (arachidonyltrifluoromethyl ketone), but neither by p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] nor by nuclear factor-kappaB (NF-kappaB) inhibitory peptide NF-kappaB SN50 (H-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-Val-Gln-Arg-Lys-Arg-Gln-Lys-Leu-Met-Pro-OH). IL-1beta significantly increased the phosphorylation of extracellular signal-regulated kinase 1 (ERK1)/ERK2 MAPKs and cPLA(2) and IL-1beta-induced cPLA(2) phosphorylation was blocked by PD98059. We conclude that Ca(2+) stores of HSCM cells may be reduced in ulcerative colitis and that the signal transduction pathway of neurokinin A-induced contraction switches from calmodulin- and protein kinase C-dependent in normal cells to protein kinase C-dependent in ulcerative colitis cells. IL-1beta reproduces these changes, possibly by production of H(2)O(2) via sequential activation of MAPKs (ERK1/ERK2) and cPLA(2).
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PMID:Interleukin 1beta-induced production of H2O2 contributes to reduced sigmoid colonic circular smooth muscle contractility in ulcerative colitis. 1520 51

We investigated whether substance P modulates pacemaker currents generated in cultured interstitial cells of Cajal of murine small intestine using whole cell patch-clamp techniques at 30 degrees C. Interstitial cells of Cajal generated spontaneous inward currents (pacemaker currents) at a holding potential of -70 mV. Tetrodotoxin, nifedipine, tetraethylammonium, 4-aminopyridine, or glibenclamide did not change the frequency and amplitude of pacemaker currents. However, divalent cations (Ni2+, Mn2+, Cd2+, and Co2+), nonselective cationic channel blockers (gadolinium and flufenamic acid), and a reduction of external Na+ from normal to 1 mM inhibited pacemaker currents indicating that nonselective cation channels are involved in their generation. Substance P depolarized the membrane potential in current clamp mode and produced tonic inward pacemaker currents with reduced frequency and amplitude in voltage clamp mode. [D-Arg1, D-Trp7,9, Leu11] substance P, a tachykinin NK1 receptor antagonist, blocked these substance P-induced responses. Furthermore, [Sar9, Met(O2)11] substance P, a specific tachykinin NK1 receptor agonist, depolarized the membrane and tonic inward currents mimicked those of substance P. Substance P continued to produce tonic inward currents in external Ca2+-free solution or in the presence of chelerythrine, a protein kinase C inhibitor. However, substance P-induced tonic inward currents were blocked by thapsigargin, a Ca2+-ATPase inhibitor in the endoplasmic reticulum or by an external 1 mM Na+ solution. Our results demonstrate that substance P may modulate intestinal motility by acting on the interstitial cells of Cajal by activating nonselective cation channels via the release of intracellular Ca2+ induced by tachykinin NK1 receptor stimulation.
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PMID:Substance P induces inward current and regulates pacemaker currents through tachykinin NK1 receptor in cultured interstitial cells of Cajal of murine small intestine. 1521 18

Neurokinins such as substance P and neurokinin A have long been thought to act as neurotransmitters or modulators in the nucleus tractus solitarius. However, the role and location of the receptors for these peptides have remained unclear. We examined the consequences of activation of the neurokinin-1 (NK1) receptor subtype in the rat nucleus tractus solitarius using whole-cell patch clamp recordings in brain slices. Application of delta-Ala-Phe-Phe-Pro-MeLeu-D-Pro[spiro-gamma-lactam]-Leu-Trp-NH2 (a specific NK1 agonist) or neurokinin A resulted in depolarization, evident as a slow inward current, mediated by direct postsynaptic NK1 receptor activation. The effect was conserved in the presence of tetrodotoxin, and protein kinase C-dependent since it was blocked by 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl)maleimide, a specific protein kinase C inhibitor. In addition, an increase in the frequency and amplitude of spontaneous excitatory postsynaptic currents was observed, reflecting increased glutamate release induced by NK1 receptor activation. This effect was abolished by tetrodotoxin, suggesting that it resulted from increased firing in afferent neurons, subsequent to somatodendritic excitation via NK1 receptors. Furthermore, spontaneous inhibitory postsynaptic currents were increased in frequency and amplitude showing that GABA release was promoted by NK1 receptor activation. However, amplitude of miniature inhibitory postsynaptic currents was unaltered by NK1 receptor activation, but the increase in frequency persisted. These findings suggest that NK1 receptors are located on presynaptic terminals as well as at somatodendritic sites of GABAergic neurons. The increase in GABA release was also shown to be protein kinase C-dependent. The data presented here show NK1 receptors in the rat nucleus tractus solitarius are present both excitatory and inhibitory neurons. Activation of these receptors can result in increases in release of both GABA and glutamate, suggesting a crucial modulatory role for NK1 receptors in the rat nucleus tractus solitarius.
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PMID:Neurokinin-1 receptors in the rat nucleus tractus solitarius: pre- and postsynaptic modulation of glutamate and GABA release. 1526 36


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