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)

The common pathway of heterogenous mast cell activation as mediated by antigens is through the cross-linking of IgE bound to Fc epsilon RI receptors. The peptidergic pathway of mast cell activation, achieved by cationic secretagogues, is restricted to "serosal" mast cells, the experimental models being rat peritoneal and human skin mast cells. Cationic secretagogues include positively charged peptides but also various amines such as compound 48/80 and natural polyamines. An early intracellular event of this pathway is the activation of pertussis toxin-sensitive G proteins. The correlation observed between the ability of basic compounds to trigger mast cell exocytosis and their potency to activate purified G proteins strongly suggests that cationic compounds activate mast cell G proteins via a receptor-independent but membrane-assisted process. In this paper, alternative mechanisms are discussed. The consequence of G protein stimulation is the activation of phospholipase C with an increase in inositol triphosphates. Natural polyamines are relatively poor triggers of mast cells (10(-4) to 10(-2) M). Neuropeptides such as substance P, neuropeptide Y or vasoactive intestinal peptide, peptidic hormones such as kinins, and venoms such as mastoparan and mast cell degranulating peptide, are all active in a concentration range from 10(-7) to 10(-4) M. The cationic anaphylatoxin C3a also stimulates mast cells at concentrations below precursor complement C3 blood levels. The component C3 of the complement system is one of only a few plasma proteins having activation fragments (i.e. C3a) that can be generated at micromolar levels. The effects of basic secretagogues defines a peptidergic pathway of mast cell activation, which represents a potentially toxic process considering the tissue effects caused by exogenous basic compounds such as venom peptides and certain amine containing drugs. Peptidergic activation of mast cells may also be a pathophysiological process having an important role in neurogenic inflammation and in diseases involving extensive activation of the blood complement cascade.
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PMID:Peptidergic pathway in human skin and rat peritoneal mast cell activation. 751 63

1. The effect of exogenous dopamine on the release of endogenous acetylcholine (ACh) from isolated ileal synaptosomal guinea-pig preparations was examined by means of high pressure liquid chromatography with electrochemical detection. 2. Release of ACh was induced by substance P or by depolarization with high potassium (50 mM) in a medium containing atropine propranolol and naloxone. 3. Dopamine produced a concentration-dependent inhibition of the evoked ACh release induced by substance P or in samples depolarized by high potassium. This action of dopamine was not reversed by the dopamine receptor antagonists either for the DA2 subtype domperidone, or for the DA1 subtype, SCH23390. Fenoldopam, the agonist of dopamine DA1 receptors, or quinpirole, the agonist of dopamine DA2 receptors, reduced the evoked ACh release, although only in high, non-dopamine-specific concentrations. 4. Failure of guanethidine or desipramine to inhibit this effect of dopamine ruled out mediation by endogenous noradrenaline. 5. Idazoxan and yohimbine reversed this dopamine-induced inhibition at concentration sufficient to abolish the action of clonidine. Influx of (45)Ca stimulated by substance P or high potassium into synaptosomal preparations was attenuated in the presence of dopamine. This inhibition by dopamine was also reversed by idazoxan or yohimbine but not by dopamine receptor antagonists. Moreover, the dopamine-induced inhibitions of both the ACh release and the influx of (45)Ca disappeared in the samples treated with pertussis toxin at a dose sufficient to abolish the action of clonidine. 6. It is concluded that dopamine suppresses the influx of calcium ions into cholinergic nerve terminals via an activation of alpha2-adrenoceptors coupled with a pertussis toxin-sensitive GTP-binding protein, resulting in the decrease of ACh release from ileal synaptosomes of guinea-pigs.
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PMID:Dopamine-induced inhibition of endogenous acetylcholine release from the isolated ileal synaptosomal preparations of guinea-pig mediated via alpha-adrenoceptors. 752 17

Variations in intracellular free calcium concentration (delta[Ca2+]i) were measured in intact and isolated human astrocytoma cells (U373 MG) loaded with fura-2 acetoxymethylester. Microperfusion of 50 nM substance P (SP), applied for 1 s, increased [Ca2+]i by 351 nM from a stable basal level of [Ca2+]i of 26 nM. The peak delta[Ca2+]i induced by SP was dose dependent with a threshold of 10(-3) nM, an ED50 of 1.3 nM and a maximal effect for concentrations of SP greater than 100 nM. The NK1 receptor agonist, [Sar9Met(O2)11]SP, mimicked the effect of SP, while the NK2 and NK3 selective receptor agonists, [N1(10)]NKA(4-10) and senktide, respectively, had no effect. The delta[Ca2+]i induced by SP was unaffected by 100 microM cadmium or by removal of extracellular calcium ions. Caffeine up to 30 mM had no effect on [Ca2+]i. In contrast, thapsigargin increased resting [Ca2+]i by 92 nM and reduced the delta[Ca2+]i induced by SP. A pertussis treatment (500 ng/ml-24 h) did not modify the delta[Ca2+]i induced by SP. We conclude that SP, acting on a NK1 receptor, mobilizes cytosolic calcium from an intracellular calcium pool which can be partially depleted by thapsigargin.
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PMID:Mobilization of intracellular calcium by substance P in a human astrocytoma cell line (U-373 MG). 752 79

The actions of N-ethylmaleimide (NEM), a sulfhydryl alkylating agent, on G-protein-mediated inhibition of N-type Ca2+ channels in adult rat superior cervical ganglion (SCG) neurons were studied using whole-cell voltage clamp. In SCG neurons, inhibition of ICa occurs by at least three separable pathways: one pertussis toxin (PTX) sensitive and voltage dependent, and two PTX insensitive and voltage independent. NEM blocked PTX-sensitive inhibition nearly completely, with only small effects on PTX-insensitive inhibition. Somatostatin inhibition is completely PTX sensitive and was wholly blocked by a 120 sec exposure to 50 microM NEM, with shorter exposure times producing a less complete block. Inhibition of ICa by norepinephrine (NE) is approximately half PTX sensitive and was also approximately half NEM sensitive. One component of muscarinic inhibition is PTX insensitive, voltage independent, and mediated by a diffusible cytoplasmic messenger; this pathway was largely spared by NEM treatment. Another pathway is also PTX insensitive and voltage independent, used by substance P, and was also largely NEM insensitive. Hence, in SCG neurons, NEM selectively inactivates PTX-sensitive G-proteins. We also find evidence that the PTX-insensitive action of NE is distinct from the other PTX-insensitive pathways, and therefore assign it to a fourth signaling pathway.
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PMID:Modulation of Ca2+ channels by PTX-sensitive G-proteins is blocked by N-ethylmaleimide in rat sympathetic neurons. 752 95

Intracellular recordings were made in submucosal neurons from the guinea pig ileum to study the actions of norepinephrine and somatostatin on slow depolarizations induced by 2-chloroadenosine (CADO) and substance P. Local application (by pressure) of CADO and substance P induced a slow depolarization that occurred concomitantly with an increase in input membrane resistance. Norepinephrine, UK-14304 (alpha 2-adrenoceptor agonist), and somatostatin blocked the excitatory responses induced by CADO in a concentration-dependent manner. The alpha 2-adrenoceptor antagonists idazoxan and yohimbine antagonized these inhibitory effects of UK-14304 and norepinephrine. UK-14304 also decreased depolarizations induced by forskolin, but not those induced by the adenosine 3',5'-cyclic monophosphate analogue 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate. Slow depolarizations induced by substance P were blocked neither by UK-14304 nor by somatostatin. It was previously shown that staurosporine (an inhibitor of various protein kinases) and KT-5720 (an inhibitor of protein kinase A) inhibited slow depolarizations induced by CADO. Here, substance P depolarizations were inhibited by staurosporine and calphostin C (a blocker of protein kinase C) but not by KT-5720. In conclusion, activation of alpha 2-adrenoceptors and somatostatin receptors selectively blocks excitatory responses induced by CADO, most likely by inhibition of adenylyl cyclase and via pertussis toxin-sensitive G proteins. Slow depolarizations induced by substance P are independent of adenylyl cyclase activation and involve activation of protein kinase C.
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PMID:Interactions between inhibitory and excitatory modulatory signals in single submucosal neurons. 752 97

We investigated the release of [3H]arachidonic acid ([3H]AA) and its relationship to the formation of [3H]inositol trisphosphate ([3H]IP3) elicited by substance P (SP) in prelabeled Chinese hamster ovary cells stably expressing the SP receptor. Activation of the SP receptor resulted in a concentration- and time-dependent stimulation of [3H]AA release. Half-maximal release was obtained at 10(-9) M, comparable to that for [3H]IP3 formation reported previously, and the maximal release effected by 0.1 microM SP was 8 to 10-fold above the basal value. Both the [3H]AA release and the [3H]-IP3 accumulation stimulated in the cells by 0.1 microM SP were concentration-dependently blocked with the specific SP receptor antagonist CP-96,345, with IC50 values of 2.5 and 0.4 microM, respectively. The time course of [3H]AA release showed a biphasic pattern: an initial rapid release essentially independent of Ca2+, followed by a sustained release markedly suppressed by removal of extracellular Ca2+ or chelation of intracellular Ca2+ with 1,2-bis(2-aminophenoxyethane)-N,N,N',N'-tetraacetic acid (BAPTA). While pretreatment with pertussis toxin (200 ng/mL, 6 hr) did not block [3H]IP3 formation, it did reduce [3H]AA release by 50% at 1 and 10 min after SP stimulation. Treatment of the cells with a phorbol ester, a protein kinase C activator, augmented the SP-stimulated [H]AA release, and sphingosine, a protein kinase C inhibitor, reversed the phorbol ester-potentiated [3H]AA release, but not the release stimulated by SP alone, suggesting a synergistic effect of protein kinase C on SP-stimulated AA release. These results demonstrate that SP, acting at the SP receptor, stimulates [3H]AA release via mechanisms that are (1) mediated by a pertussis toxin-sensitive G-protein, (2) dependent on extracellular Ca2+, and (3) enhanced by activation of protein kinase C.
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PMID:Multiple mechanisms of arachidonic acid release in Chinese hamster ovary cells transfected with cDNA of substance P receptor. 752 67

In locus coeruleus neurons, substance P (SP) suppresses an inwardly rectifying K+ current via a pertussis toxin-insensitive guanine nucleotide binding protein (G protein; GnonPTX), whereas somatostatin (SOM) or [Met]enkephalin (MENK) enhances it via a pertussis toxin-sensitive G protein (GPTX). The interaction of the SP and the SOM (or MENK) effects was studied in cultured locus coeruleus neurons. In neurons loaded with guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]), application of SOM (or MENK) evoked a persistent increase in the inward rectifier K+ conductance. A subsequent application of SP suppressed this conductance to a level less than that before the SOM (or MENK) application; the final conductance level was independent of the magnitude of the SOM (or MENK) response. This suppression by SP was persistent, and a subsequent SOM (or MENK) application did not reverse it. When SP was applied to GTP[gamma S]-loaded cells first, subsequent SOM elicited only a small response. In GTP-loaded neurons, application of SP temporarily suppressed the subsequent SOM- (or MENK)-induced conductance increase. These results suggest that the same inward rectifier molecule that responds to an opening signal from GPTX also responds to a closing signal from GnonPTX. The closing signal is stronger than the opening signal.
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PMID:Opposing mechanisms of regulation of a G-protein-coupled inward rectifier K+ channel in rat brain neurons. 753 96

It has recently been shown that two novel tachykinins, ranakinin and [Leu3, Ile7]neurokinin A, are present in fibers innervating the frog adrenal gland, and it has been demonstrated that tachykinins stimulate corticosteroid secretion in vitro through activation of chromaffin cells. The purpose of the present study was to investigate the effect of ranakinin on cytosolic free calcium concentrations ([Ca2+]i) and to determine the source of calcium involved. Cultured adrenal cells were loaded with the fluorescent calcium indicator indo-1, and changes in [Ca2+]i were studied using dual emission wavelength microfluorimetry. Administration of a brief pulse of ranakinin (1 microM; 1 sec) in the vicinity of chromaffin cells caused an immediate and transient increase in [Ca2+]i. Repeated pulses of ranakinin resulted in a gradual decline in the [Ca2+]i response, suggesting the occurrence of a desensitization phenomenon. Preincubation of the cells with the calcium channel blockers nifedipine (10 microM) and omega-conotoxin (1 microM) did not alter the response of chromaffin cells to ranakinin. Chelation of extracellular calcium by EGTA (10 mM) caused a marked decrease in the basal [Ca2+]i, but did not suppress the ranakinin-induced [Ca2+]i increase. Conversely, incubation of the cells with thapsigargin (10 microM), an inhibitor of calcium adenosine triphosphatase activity, abolished the stimulatory effect of ranakinin, indicating that the increase in [Ca2+]i can be ascribed to mobilization of calcium from intracellular stores. Preincubation of adrenal cells with the phospholipase C antagonist U-73122 (1 microM; 18 min) or with pertussis toxin (10 microM; 18 h) totally blocked the ranakinin-induced [Ca2+]i rise. Taken together, these data indicate that in frog adrenochromaffin cells, ranakinin causes mobilization of calcium from intracellular stores. The effect of ranakinin is mediated through activation of a phospholipase C via a pertussis toxin-sensitive G protein.
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PMID:Effect of ranakinin, a novel tachykinin, on cytosolic free calcium in frog adrenochromaffin cells. 766 74

We studied inhibition of N-type Ca2+ channels in rat superior cervical ganglion neurons by substance P (SP) and somatostatin-14 (Som). In whole-cell clamp, 70 of 82 acutely dissociated neurons showed inhibition (mean 37%) by 500 nM SP, and 54 of 61 showed inhibition by 240 nM Som (mean 57%). Pertussis toxin (PTX) blocked Som but not SP inhibition; intracellular dialysis with 2 mM GDP-beta-S attenuated inhibition with either peptide. Inhibition was voltage dependent with Som but not with SP. Neurokinin A (1 microM) or B was without effect, implicating NK1 tachykinin receptors. In cell-attached patches with bath-applied drugs, to test for a diffusible messenger, inhibition by SP or Som was only 8%. Thus, SP signaling is voltage independent and PTX insensitive; Som inhibition is voltage dependent and PTX sensitive; and both are membrane delimited.
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PMID:Substance P and somatostatin inhibit calcium channels in rat sympathetic neurons via different G protein pathways. 767 64

The effects of pretreatment with pertussis toxin (PTX) on the sedative effect of morphine administered i.c.v. (200 nmol), and on the locomotor and behavioural activation precipitated by naloxone (15 mg/kg s.c.) following treatment with a single dose of morphine (i.c.v., 200 nmol), were investigated in guinea-pigs. Responses to i.c.v. administration of substance P (50 nmol), quinpirole (200 nmol), U50,488H (100 nmol) and carbachol (2 nmol) following PTX pretreatment were also investigated. Following PTX pretreatment, morphine induced mild agitation and the onset of sedation was delayed. Pretreatment with PTX also attenuated the locomotor and some components of behavioural activation induced by substance P, U50,488H, quinpirole and naloxone-precipitated morphine withdrawal, but failed to attenuate the effects induced by carbachol. These results suggest the involvement of PTX-sensitive G-protein-mediated mechanisms in the sedative effect of morphine in guinea-pigs and in the central stimulating actions of acute morphine withdrawal, U50,488H, substance P, and quinpirole.
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PMID:Effects of pertussis toxin on behavioural responses of guinea-pigs to centrally administered substance P, quinpirole, carbachol, U-50,488H, morphine and morphine withdrawal. 768 Mar 19


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