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

1. The aim of this study was a pharmacological characterization of the multiple NANC inhibitory transmission systems producing relaxation of the circular muscle of guinea-pig proximal colon. In the presence of atropine (1 microM), guanethidine (3 microM) and of the tachykinin NK1 and NK2 receptor antagonists, SR 140333 (0.3 microM) and MEN 10627 (1 microM), respectively, electrical field stimulation (EFS) produced a frequency-dependent (0.1-3 Hz) relaxation. During a cumulative frequency-response curve, the maximal relaxant effect was produced at 3 Hz and approached the maximal relaxation to 1 microM isoprenaline. In the presence of both apamin (0.3 microM) and L-nitroarginine (L-NOARG, 100 microM), EFS failed to evoke relaxation up to 1 Hz; at 1-10 Hz, a slowly developing relaxation ensured which approached 50% of the Emax to isoprenaline. The EFS-evoked NANC relaxation, either in the presence or absence of apamin and L-NOARG, was unaffected by in vitro capsaicin pretreatment (10 microM for 15 min). 2. Three protocols of EFS were developed for further pharmacological analysis: (a) EFS at 1 Hz for 5 s in the presence of L-NOARG, producing a transient fast apamin-sensitive relaxation; (b) EFS at 1 Hz for 5 s in the presence of apamin, producing a transient fast L-NOARG-sensitive relaxation; and (c) EFS at 10 Hz for 5 s in the presence of both apamin and L-NOARG, producing a transient but slowly developing and more sustained relaxation. 3. The neutral endopeptidase inhibitor, thiorphan (1-10 microM), enhanced and prolonged the apamin- and L-NOARG-resistant NANC relaxation produced by EFS at 10 Hz, without affecting that evoked at 1 Hz in the presence of apamin or L-NOARG. The angiotensin converting enzyme inhibitor, captopril (1-10 microM) was without effect. 4. The cAMP analogue inhibitor of protein kinase A, Rp-cAMPs (100-300 microM) significantly reduced and shortened the NANC relaxation produced by 10 Hz EFS in the presence of L-NOARG without affecting that produced by 1 Hz EFS in the presence of apamin or L-NOARG. 5. The inhibitor of sarcoplasmic reticulum Ca-ATPase, cyclopiazonic acid (CPA, 3-10 microM for 60 min) abolished the 1 Hz EFS-induced relaxation in the presence of L-NOARG, and greatly inhibited that produced by 10 Hz EFS in the presence of both apamin and L-NOARG. The relaxation produced by 1 Hz EFS in the presence of apamin was inhibited by about 32% at 10 microM only. 6. Nifedipine (1 microM) did not affect the EFS-induced NANC relaxations. In the presence of nifedipine, tetraethylammonium (TEA, 1 mM) enhanced the 1 Hz EFS-induced relaxation in the presence of L-NOARG (158% of control) and that produced by 10 Hz EFS in the presence of apamin and L-NOARG (215% of control) while that evoked by 1 Hz EFS in the presence of apamin was slightly affected (109% of control). 7. In the presence of atropine, guanethidine, SR 140333 and MEN 10627, bath application of human vasoactive intestinal polypeptide (VIP, 0.1 nM-10 nM) produced a concentration-dependent, slowly developing relaxation of colonic strips. The relaxation to VIP was unaffected by apamin (0.3 microM), L-NOARG (100 microM), nifedipine (1 microM) or nifedipine plus TEA (1 mM); it was inhibited by CPA (10 microM) and Rp-cAMPs (100 microM) and was potentiated by thiorphan (10 microM). 8. The putative VIP receptor antagonist, VIP(10-28) (10 microM) did not affect the VIP-induced relaxation nor the NANC relaxation to 10 Hz EFS in the presence of apamin and L-NOARG. 9. The present findings provide evidence that three distinct NANC inhibitory mechanisms mediate relaxation of the circular muscle of the guinea-pig proximal colon. The first system provides a fast relaxation in response to low frequency of stimulation and may involve the action of a transmitter(s) (possibly ATP) which mobilizes intracellular Ca2+ from sarcoplasmic reticulum leading to the activation of apamin-sensitive K+ channels. The second system likewise provides a fast relaxation of the colon in
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PMID:Characterization of the apamin- and L-nitroarginine-resistant NANC inhibitory transmission to the circular muscle of guinea-pig colon. 888 60

1. Phosphorylation of caldesmon was assayed in canine colonic circular smooth muscle strips labelled with 32P and stimulated with 10 microM acetylcholine. Caldesmon was isolated by two-dimensional non-equilibrium pH gel electrophoresis. Stimulation with acetylcholine increased caldesmon phosphorylation significantly from a basal level of 0.6 +/- 0.07 to 1.1 +/- 0.15 mol P1 (mol caldesmon)-1 after 2 min. 2. MAP kinase activities were measured in SDS extracts of muscle by a gel reconstitution method using myelin basic protein. Myelin basic protein kinase activities were observed at 38, 44, 50 and 57 kDa by the gel reconstitution method. Endogenous caldesmon kinase activities were also identified by the gel reconstitution method at 38, 44 and 50 kDa. The 38 and 44 kDa kinases comigrated with proteins labelled by anti-ERK1 MAP kinase antibodies on Western blots. Both 38 and 44 kDa MBP kinase activities increased significantly during contractions induced by 10 microM acetylcholine, 0.1 microM neurokinin A and 70 mM potassium. 3. Phorbol dibutyrate (0.1 microM) potentiated activation of MAP kinases and contraction of depolarized muscles while producing a decrease in fura-2 fluorescence ratio. This suggests that protein kinase C activation is coupled to MAP kinase activity in colonic smooth muscle. 4. MAP kinases isolated form muscle homogenates by Mono Q chromatography were assayed using the specific MAP kinase substrate peptide APRTPGGRR. Stimulation of muscles for 2 min with 10 microM acetylcholine activated both ERK1 and ERK2 MAP kinase activities 2-fold. 5. To determine the effects of caldesmon phosphorylation by MAP kinase on the cross-bridge cycle, actin sliding velocity was measured with an in vitro motility assay. Unphosphorylated turkey gizzard caldesmon (3 microM) significantly reduced mean sliding velocity. Phosphorylation of caldesmon with sea star ERK1 MAP kinase reversed the inhibitory effect of caldesmon on sliding velocity. The results are consistent with a protein kinase cascade being activated by contractile agonists in gastrointestinal smooth muscle which activates ERK MAP kinases leading to phosphorylation of caldesmon. Phosphorylation of caldesmon in vivo may reverse inhibitory influences of caldesmon on cross-bridge cycling.
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PMID:Activation of MAP kinases and phosphorylation of caldesmon in canine colonic smooth muscle. 888 69

1. The effects of substance P (SP) and related tachykinins on the function of gamma-aminobutyric acid-A (GABAA) receptors were examined in acutely dissociated neurones of bullfrog dorsal root ganglia (DRG) by using whole-cell voltage-clamp techniques. 2. Application of SP (10 nM to 1 microM) depressed inward currents produced by GABAA receptor activation (IGABA). Neurokinin A (NKA) and neurokinin B (NKB) also depressed IGABA; the rank order of agonist potency was SP > NKA > NKB. Spantide ([D-Arg1, D-Trp7,9,Leu11]SP) and L-703,606, NK1 receptor antagonists, blocked the SP-induced depression of IGABA. 3. SP irreversibly depressed IGABA, when neurones were intracellularly dialysed with GTP gamma S. Intracellular application of GDP beta S prevented the SP-induced depression of IGABA. Pertussis toxin (PTX) did not block the inhibitory effect of SP on IGABA. 4. The depression of IGABA produced by SP was inhibited by H-7 and PKC(19-36), protein kinase C (PKC) inhibitors, but not by H-9 and HA-1004, protein kinase A inhibitors. IGABA was suppressed by application of sn-1,2-dioctanoyl glycerol (DOG), a PKC activator. 5. It is concluded that activation of neurokinin-1 (NK1) receptors downregulates the function of the GABAA receptor of primary sensory neurones through a PTX-insensitive G-protein. PKC may be involved in the transduction pathway of the tachykinin-induced inhibition of the GABAA receptor.
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PMID:Substance P suppresses GABAA receptor function via protein kinase C in primary sensory neurones of bullfrogs. 891 Feb 28

The carboxy-terminal cytoplasmic regions of the rat neurokinin 1 (substance P) and neurokinin 2 (neurokinin A) receptors have been exchanged to determine if this region of the neurokinin 1 receptor is involved in its desensitization. When expressed at similar levels in stably transfected Chinese hamster ovary (CHO) cell lines, receptors containing the carboxy-terminal region of the neurokinin 1 receptor desensitized significantly more (as measured by reduction of the inositol 1,4,5-trisphosphate response) when preexposed for 1 min to 1 microM neurokinin, indicating a role for the carboxy-terminal region of the neurokinin 1 receptor in its desensitization. Measurement of receptor internalization using radiolabeled neurokinins (0.3 nM) indicated that approximately 75-80% of the receptors were internalized in each cell line after 10 min at 37 degrees C, with no observable correlation between neurokinin receptor desensitization and internalization. Measurement of loss of receptor surface sites for cell lines CHO NK1 and CHO NK1NK2 following exposure to 1 microM substance P also indicated no obvious relationship between the percent desensitization and percent of receptors internalized. Also, two inhibitors of neurokinin 1 receptor internalization, phenylarsine oxide and hyperosmolar sucrose, did not inhibit neurokinin 1 receptor desensitization. The protein kinase inhibitors Ro 31-8220, staurosporine, and Zn2+ had no effect on neurokinin 1 receptor desensitization, indicating that the kinases affected by these agents are not rate-limiting in neurokinin 1 receptor desensitization in this system.
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PMID:Desensitization of the neurokinin 1 receptor is mediated by the receptor carboxy-terminal region, but is not caused by receptor internalization. 893 68

We examined the mechanisms of the inhibitory effects of calcitonin gene-related peptide (CGRP) on substance-P-induced superoxide anion (O2-) production in human neutrophils. Substance P (30 microM) caused O2- production associated with an inositol-1,4,5-trisphosphate (IP3)-induced transient increase in intracellular Ca2+ concentrations ([Ca2+]i). CGRP (10 microM) significantly inhibited substance-P-induced O2- production and transient increase in [Ca2+]i, but it only slightly suppressed IP3 formation. In addition, CGRP inhibited IP3-induced O2- production and transient increase in [Ca2+]i, caused by exogenous addition of IP3 in saponin-permeabilized neutrophils. These findings suggest that CGRP inhibits the response of neutrophils to substance P through the inhibition of IP3-induced Ca2+ release from intracellular Ca2+ stores. The inhibitory effects of CGRP on substance P- or IP3-induced O2- production and increases in [Ca2+]i were abolished by pretreating the neutrophils with a CGRP receptor antagonist, CGRP-(8 - 37), or cyclic AMP (cAMP)-dependent protein kinase inhibitors, N-[2-(methylamino) ethyl]-5-isoquinoline-sulfonamide dihydrochloride (H-8) and 9-n-hexyl ester derivative of K-572a (8R, 9S, 11 S)-(--)-9-hydroxy-9-methoxycarbonyl-8-methyl-8-methyl-2,3,9,10- tetrahydro-8,11-epoxy-1H,8H, 11 H-2,7b,11a-triazadibenzo (a,g)cycloocta(cde)trinden-1-one (KT5720). We concluded that CGRP receptor stimulation reduces substance-P-induced O2- production by the inhibition of IP3-induced transient increase in [Ca2+]i, probably via the phosphorylation of IP3 receptor by cAMP-dependent protein kinase.
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PMID:Inhibitory effects of calcitonin gene-related peptide on substance-P-induced superoxide production in human neutrophils. 895 34

We have investigated cross-talk between the cAMP/protein kinase A (PKA) and protein kinase C (PKC)/inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) messenger systems probed by vasoactive intestinal peptide (VIP) and substance P (SP), respectively, in rat pituitary cell cultures enriched in lactotrophs. VIP and forskolin had no effect on the basal distribution pattern of the four PKC isozymes (alpha, beta, delta, and zeta) detectable in lactotroph-enriched cell cultures derived from peripubertal male rats, whereas both compounds significantly increased translocation of PKC alpha and beta from the cytosol to the plasma membrane induced by SP. The delta and zeta subspecies were not affected by VIP and forskolin. Moreover, VIP and forskolin also stimulated SP-induced formation of Ins(1,4,5)P3 while having no effect on basal inositol phosphate turnover. The effects of VIP and forskolin on PKC isozyme distribution could be blocked by pretreating cells with the PKA inhibitor rp-cAMP. On the other hand, SP potentiated the effect of VIP and forskolin on cAMP formation while having no effect on the cAMP pathway when it was not triggered by an appropriate agonist. Down-regulation of PKC activity by long term 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment (24 h) diminished, but did not abolish, the effect of SP on VIP-stimulated cAMP production. Staurosporine and dopamine inhibited the potentiating effect of SP on cAMP accumulation. TPA, which translocates PKC alpha, beta, and delta in lactotrophs, had a synergistic effect on cAMP formation induced by VIP, but did also, unlike SP, display cAMP rising abilities when cells were not exposed to VIP and forskolin. Discharging intracellular Ca2+ by thapsigargin pretreatment had no effect on the basal cAMP concentration or the VIP-induced cAMP response, whereas exposure of cells to SP, thapsigargin, and VIP resulted in a decrease of the cAMP response compared with SP + VIP. The potentiating effect of SP on the VIP response could also be inhibited, but not blocked, by staurosporine. On the basis of these results, it is concluded that there exists substantial cross-talk between the cAMP/PKA and PKC/Ins(1,4,5)P3 messenger systems in lactotroph-enriched cell cultures. Key effectors seem to be PKA, one or more of PKC alpha, beta, deleta and Ins(1,4,5)P3-sensitive Ca2+ stores.
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PMID:Cross-talk between cellular signaling pathways activated by substance P and vasoactive intestinal peptide in rat lactotroph-enriched pituitary cell cultures. 907 34

Substance P (SP) did not affect either basal or agonist-stimulated aldosterone production by dispersed rat zona glomerulosa (ZG) cells. In contrast, the SP-receptor antagonist spantide-II (SPA), at 10(-8)/10(-6) M concentrations, markedly raised basal and 10(-9) M ACTH, but not 10(-9) M angiotensin II-stimulated aldosterone secretion. The secretagogue effect of 10(-6) M SPA was annulled by SP (10(-6) M) and the protein kinase (PK)-C inhibitor Ro31-8220 (10(-6) M), but was unaffected by the PKA inhibitor H-89 (10(-5) M). In light of these findings the following conclusions can be drawn: (i) SP does not exert a physiologically relevant direct modulatory action on aldosterone secretion of rat ZG cells; (ii) a receptor-independent inhibitory interaction is likely to occur between SP and SPA molecules; and (iii) SPA activates, through a receptor-independent mechanism, phosphoinositide signaling pathway in rat ZG cells.
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PMID:Stimulatory effect of the substance P antagonist spantide-II on aldosterone secretion of dispersed rat zona glomerulosa cells. 918 44

The present study deals with the effects of withdrawal of dopamine (DA) on the translocation of protein kinase C (PKC) isozymes and release of prolactin (Prl) in resting- and substance P (SP)-stimulated cultures of enriched rat pituitary lactotrophs. Following a brief tonic input (10 min), DA withdrawal induced a redistribution of PKC alpha- and beta-immunoreactivity (IR) to the particulate fraction with maximal levels, attained after 5 min, remaining translocated for 20 min. DA withdrawal prolonged the effect of SP-induced translocation of PKC alpha- and beta-IR. Similar effects were detected when the catalytic activity of PKC in response to DA withdrawal was evaluated. Thus, DA washout redistributed PKC catalytic activity and prolonged the effect of SP on catalytical PKC translocation to the particulate fraction. Pretreatment of cells with the protein kinase A inhibitor, rp-adenosine-3',5'-cyclic monophosphothionate (rp-cAMP), reduced the amount of PKC alpha- and beta-IR redistributed after DA withdrawal. Furthermore, this treatment also reduced the DA withdrawal effect on SP-mediated translocation of PKC alpha- and beta-IR. Methoxyverapamil, a blocker of voltage-gated Ca2+ channels, completely inhibited the redistribution of PKC isozymes after DA withdrawal, but also reduced the potentiating effect of DA withdrawal on SP-induced redistribution of PKC isozyme-IR. In perifused enriched lactotrophs, DA withdrawal induced a release of Prl that lasted 45-55 min and prolonged the effect of SP on Prl secretion. rp-cAMP did not significantly affect Prl release due to DA removal, but the prolonging effect of DA withdrawal on SP-induced Prl secretion was abolished. Methoxyverapamil completely abolished the rebound release of Prl after DA withdrawal, and the potentiating effect of DA removal on SP-mediated Prl release was also diminished. Readdition of DA after DA withdrawal was able to suppress the translocation of PKC isozyme-IR and catalytic activity and to reduce the release of Prl to baseline levels. Moreover, readdition of DA reduced the potentiating effects of DA withdrawal on the same parameters after SP-stimulation of cells. On the basis of these results it is concluded that in resting cells following DA withdrawal prolactin is released and specific PKC isozymes and concomitant catalytic activity are translocated to the particulate fraction in enriched lactotrophs. While cAMP/PKA and influx of Ca2+ seem to work in concert in translocating PKC, influx of Ca2+ is the primary mechanism responsible for the rebound release of Prl after DA withdrawal. DA withdrawal exerts a potentiating effect on SP-induced PKC translocation and Prl release. It is suggested that the biochemical events involved in these processes are cAMP/PKA and Ca2+ influx.
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PMID:Effects of withdrawal of dopamine on translocation of protein kinase C isozymes and prolactin secretion in rat lactotroph-enriched pituitary cells. Modulation of substance P-mediated responses. 919 72

Four tachykinin-related peptides, locustatachykinin 1-4 (LomTK 1-4) are distributed in interneurons throughout the central nervous system of the locust Locusta migratoria and may have important roles as neurotransmitters or neuromodulators. In search of the central actions of LomTKs, we analyzed the response of the efferent dorsal unpaired median (DUM) neurons in the locust metathoracic ganglion. Immunocytochemistry, using an antiserum against LomTK 1, combined with intracellular filling of efferent DUM neurons with Lucifer yellow, revealed that LomTK-immunoreactive fibers are in close proximity to dendritic arborizations of the DUM neurons. Hence, LomTKs may act on DUM neurons by releasing locally in the metathoracic ganglion. Intracellular recordings were made from somata of DUM neurons, and LomTKs were either bath-applied to an isolated metathoracic ganglion or pressure-ejected onto the DUM neuron soma. LomTK 1 at concentrations of 0.1 mM-0.1 microM caused a relatively slow, reversible depolarization with a subsequent increase in the frequency of action potential firing. Amino-terminally truncated forms of LomTK 1 were applied to DUM neurons. The heptapeptide [3-9]-LomTK 1 had a substantially reduced activity, and bioactivity was lost after further truncation. Spantide 1, an antagonist of mammalian tachykinin receptors, reversibly blocked the effect of LomTK 1. The effect of LomTK 1 was clearly reduced in the presence of GDP-beta-S, a stable analog of GDP that inactivates G-proteins. The action of LomTK 1 was potentiated by both IBMX and theophylline, two cyclic AMP (cAMP) phosphodiesterase inhibitors. The action of LomTK 1 was mimicked by pressure-ejecting 8-bromo-cAMP, a membrane permeable analog of cAMP, and by forskolin, an adenylate cyclase activator. Furthermore, cAMPS, a blocker of protein kinase A activity, reduced the effect of LomTK 1. These findings indicate that cAMP is involved in mediating DUM neuron depolarization.
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PMID:Peptidergic activation of locust dorsal unpaired median neurons: depolarization induced by locustatachykinins may be mediated by cyclic AMP. 929 67

We have examined the effects of the tachykinin substance P on the action potential of lamprey mechanosensory dorsal cells. Substance P increased the spike duration and reduced the afterhyperpolarization. These effects were mimicked by stimulation of the dorsal root, which contains tachykinin-like immunoreactive fibres. The tachykinin antagonist spantide II blocked the effects of both substance P and dorsal root stimulation. The spike broadening was voltage-dependent, and was due to the reduction of a 4-aminopyridine-sensitive potassium conductance. The spike broadening was mimicked by G-protein activators and blocked by the G-protein inhibitor GDPbetaS. Pertussis toxin did not block the effects of substance P. The spike broadening was blocked by the protein kinase C and cAMP-dependent protein kinase inhibitor H7, and by the specific protein kinase C antagonist chelerythrine, but not by the cAMP and cGMP-dependent protein kinase inhibitor H8. The phorbol ester phorbol 12,13-dibutyrate mimicked and blocked the effects of substance P, supporting the role of protein kinase C in the spike modulation. The adenylate cyclase activator forskolin and the cAMP agonist SpcAMPs mimicked but did not block the effects of substance P on the spike duration, suggesting that protein kinase A also modulates the dorsal cell action potential, but that substance P acts independently of this pathway. Substance P also increased the excitability of the dorsal cells. This effect was blocked by 4-AP, PDBu and chelerythrine, but not by H8, suggesting that the increase in excitability shares the same intracellular and effector pathways as the spike broadening.
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PMID:Substance P modulates sensory action potentials in the lamprey via a protein kinase C-mediated reduction of a 4-aminopyridine-sensitive potassium conductance. 942 Nov 67


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