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 effects of substance P (SP) on inositol trisphosphate (IP3) accumulation, myosin light chain (MLC) phosphorylation, cAMP formation and contraction were studied in iris sphincter smooth muscle of different mammalian species. SP receptor density was also examined in membrane fractions from this tissue. The data obtained can be summarized as follows. (1) In the iris sphincters of rabbit, bovine and pig, SP receptors are coupled to the phospholipase C system, whereas in dog, cat and human these receptors are coupled to the adenylate cyclase system. (2) In those species which employ the phospholipase C system, SP induced IP3 accumulation, MLC phosphorylation and contraction in a dose-dependent manner; in contrast, in those species in which SP induced the formation of cAMP we found the neuropeptide to cause muscle relaxation. The findings on cAMP formation in intact tissue were confirmed in iris sphincter membranes. Both the effect of SP on IP3 accumulation in rabbit and bovine sphincters and its effect on cAMP formation in the dog were blocked by the SP antagonist, (D-Pro2, D-Trp7, 9)-SP. (3) The density of SP receptors in rabbit, bovine and dog were found to be 227, 110.9 and 13.6 fmol mg-1 protein, respectively, and the Kd values were 1.9, 1.8 and 1.3 nM, respectively. (4) Of the neuropeptides investigated SP, neurokinin A and neurokinin B had significant stimulatory effects on IP3 accumulation and on contraction in the rabbit iris sphincter; however, neither neurokinin Y nor the calcitonin gene-related peptide (CGRP) had any effect on these responses. In addition, none of the neuropeptides studied had any effect on IP3 or on contraction in the dog iris sphincter. While it is possible that SP may have dual actions, with the predominant action dependent on the species, the data presented could suggest the presence of two SP receptor subtypes, one coupled to phospholipase C and the other to adenylate cyclase. The results of this investigation indicate major species differences in biochemical and functional responsiveness to SP and in SP receptor density in the iris sphincter of the mammalian eye, and support a modulatory role for the neuropeptide in muscle response in this tissue.
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PMID:Species differences in the effects of substance P on inositol trisphosphate accumulation and cyclic AMP formation, and on contraction in isolated iris sphincter of the mammalian eye: differences in receptor density. 172 88

Airway tissue obtained postmortem from nondiseased and severely asthmatic human lung was used in functional, radioligand binding and autoradiographic studies to investigate aspects of various receptor systems for putative mediators of asthma. Results indicate that asthma does not involve an intrinsic abnormality of smooth muscle contractility to spasmogens. Nor was there any evidence for up-regulation of histamine H1-receptor, muscarinic cholinoceptor, or alpha 1-adrenoceptor function. Conversely, severe asthma involving intense airway inflammation resulted in significant beta-adrenoceptor dysfunction, probably caused by receptor uncoupling from adenylate cyclase. Evidence was also obtained for histamine and methacholine-induced release of a nonprostanoid, airway epithelium-derived inhibitory factor (EpDIF), which may have a significant dilator effect in the adjacent bronchial circulation. The activity of this potentially protective inhibitory autacoid system would be expected to be reduced in asthma, which commonly involves epithelium damage. The autoradiographic distribution of specific binding sites for 125I-labeled substance P (I-SP) was also determined in bronchi from healthy humans and asthmatics. In sharp contrast to guinea pig airways where high levels of binding were detected over smooth muscle, specific I-SP binding was sparse over human airway smooth muscle from both sources, while dense binding was associated with structures immediately beneath the epithelium and with deep submucosal glands. These data suggest a more significant role for SP in secretory processes than in spasmogenic processes in human bronchi and highlight the potential for drawing invalid conclusions concerning human airway function from studies using animal models.
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PMID:Receptors in asthmatic airways. 215 64

Mechanisms regulating peptidergic, noradrenergic and cholinergic development were compared in dissociated cell cultures of neonatal rat sympathetic ganglia. The majority of cultured neurons contained at least two neurotransmitters and many neurons contained three or more. These studies were undertaken to determine whether co-existing transmitters were co-ordinately regulated by the environment. Co-culture of sympathetic neurons with ganglion non-neuronal cells increased substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity. Conversely, elimination of non-neuronal cells virtually abolished neuronal expression of substance P and choline acetyltransferase and increased somatostatin and tyrosine hydroxylase. Consequently, under these conditions, somatostatin and tyrosine hydroxylase were similarly regulated, whereas substance P was associated with choline acetyltransferase. By contrast, stimulation of adenylate cyclase or treatment with membrane-permeable adenosine 3',5'-phosphate analogs increased tyrosine hydroxylase and decreased choline acetyltransferase, but had no effect on substance P or somatostatin levels. Moreover, potassium- or veratridine-induced membrane depolarization increased tyrosine hydroxylase but decreased substance P, somatostatin and norepinephrine levels. However, inhibition of neurotransmitter release with magnesium or calcium-free medium prevented the decrease in norepinephrine levels but not the decrease in substance P and somatostatin. Consequently, the effects of membrane depolarization on peptide levels cannot be ascribed to release and subsequent depletion of substance P and somatostatin and must result from decreased net synthesis (synthesis minus catabolism) of the transmitters. Nerve growth-factor treatment also differentially regulated transmitter metabolism; nerve growth factor increased protein-specific activities of tyrosine hydroxylase and choline acetyltransferase but did not increase the protein-specific content of substance P and somatostatin. Quantitative transmitter expression was also influenced by neuron density; increasing density elevated substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity per neuron. Finally, culture of sympathetic neurons in a defined (serum-free) medium also altered some but not all traits, decreasing substance P, somatostatin and choline acetyltransferase without any change in tyrosine hydroxylase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential regulation of peptide and catecholamine characters in cultured sympathetic neurons. 241 73

The most important central autonomic pathways in the control of arterial blood pressure are the baroreceptor reflex pathway and descending pathways from the hypothalamus. Central neurotransmitters in these pathways are L-glutamate, substance P, norepinephrine (NE), gamma-aminobutyric acid, epinephrine, neuropeptide Y, and acetylcholine. At peripheral autonomic neurovascular junctions, there are prejunctional alpha 2- and dopamine-2 receptors, which inhibit NE release, and beta- and serotonin receptors, which stimulate NE release. Postjunctional alpha 1-receptors open sodium channels, open calcium channels via phosphoinositol release, and release intracytoplasmic calcium. Postjunctional alpha 2-receptors, which are extrasynaptic, inhibit adenylate cyclase and also open calcium channels. In animal models of hypertension, changes in alpha-receptor density have been reported. In spontaneously hypertensive rats, increased renal beta- and alpha 2-receptors, respectively, may enhance renin release and cause sodium and water retention. In experimental (renovascular) hypertension, vascular postsynaptic (vasoconstrictor) alpha 1- and alpha 2-receptors are increased. In both models of hypertension, beta-receptors are down-regulated. Selective alpha 1-antagonists, such as indoramin and prazosin, decrease arterial blood pressure by postsynaptic alpha 1-blockade; alpha 2-receptor inhibition of NE release is unaffected so that there is no beta-receptor-mediated tachycardia.
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PMID:Alpha-adrenoreceptors in hypertension. 242 93

Substance P (SP) receptors were described by the specific binding of [3H]SP to several neuronal and glial cell lines. The neuronal cell lines N18 and NG108-15 were found to contain few if any SP receptors (less than 5 fmol/mg of protein). The glial cell line LRM55 contained large numbers (Bmax = 707 fmol/mg of protein) of a single class of SP binding sites (Kd = 276 pM). [3H]SP binding could be inhibited by a number of c-terminal SP fragments and the tachykinins physalaemin, eledoisin and kassinin. The binding kinetics and pharmacology of these receptors are similar to those the authors have previously described in the brain. Activation of SP receptors was shown to inhibit cyclic AMP-dependent, beta adrenergic-stimulated taurine release from LRM55 glial cells. SP inhibition must occur by mechanisms affecting taurine release after adenylate cyclase activation, inasmuch as SP has no significant effect on beta adrenergic-stimulated increases or basal levels of intracellular cyclic AMP.
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PMID:Identification and characterization of substance P receptors on LRM55 glial cells. 242 40

A method is described for the isolation and short-term culture of canine antral gastrin (G) cells. Tissue was dispersed by enzymes and G cells enriched by elutriation and cultured for 40 h. These cultures contained 12% G cells and less than 2% somatostatin- or serotonin-containing cells. Bombesin (0.001-100 pM) potently stimulated gastrin release from cell cultures in a linear fashion over 2 h. The bombesin-specific monoclonal antibody 2A11 dose-dependently blocked bombesin stimulation. Somatostatin (0.001-1,000 nM) inhibited bombesin-stimulated gastrin release. Antibody to somatostatin (Mab S8) prevented the inhibition by exogenous somatostatin but did not alter bombesin-stimulated or basal gastrin release. The substance P (SP) analogue spantide (1 nM-1 microM) did not inhibit bombesin-stimulated gastrin release. Postreceptor activation of adenylate cyclase by forskolin and of protein kinase C by the phorbol ester, beta-TPA, caused gastrin release. The calcium ionophore A23187 also released gastrin in a dose-dependent fashion. This methodology allows enrichment and short-term culture of antral G cells; these cells have stimulatory bombesin and inhibitory somatostatin receptors, suggesting that these peptides have a direct action on antral G cells. Furthermore, G cells are activated by cAMP and calcium/phosphatidylinositol-dependent mechanisms.
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PMID:Bombesin stimulation of gastrin release from canine gastrin cells in primary culture. 243 71

Substance P, forskolin and isoprenaline stimulated rat parotid alpha-amylase secretion in vitro. Synergistic responses were observed with combinations of any two of the three secretagogues such that subthreshold doses of one caused a pronounced shift in the dose-response curve to the second. This potentiation of secretion could neither be explained by an interaction at the receptor recognition binding site, as identified by ligand binding, nor wholly by interactions in second messenger systems. Thus forskolin and isoprenaline were unable to alter substance P-induced changes in phosphatidylinositol metabolism. Similarly substance P was without effect on forskolin or isoprenaline-stimulated cAMP production. In contrast the potentiation of isoprenaline-induced amylase secretion by forskolin was preceded by a marked enhancement of cAMP production suggesting that the activation of the adenylate cyclase complex is reflected in the cellular response.
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PMID:Synergistic interactions between forskolin, isoprenaline and substance P as secretagogues in rat parotid glands. 245 34

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

Tachykinins of different classes (NK1, NK2, NK3) caused the concentration-dependent synthesis of IP3 in rat submandibular acinar cells with the potency rank order of NK1 greater than NK2 greater than NK3. Enhancement of IP3 was not affected by pertussis toxin treatment. The reverse rank order was found in the tachykinin inhibition of isoproterenol-induced cAMP synthesis and this inhibition was abolished by pertussis toxin, an inactivator of the adenylate cyclase Gi regulatory protein. It is suggested that different tachykinin receptor subtypes are preferentially coupled to phospholipase C or adenylate cyclase by separate G regulatory proteins in rat submandibular acinar cells.
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PMID:Different tachykinin receptor subtypes are coupled to the phosphoinositide or cyclic AMP signal transduction pathways in rat submandibular cells. 246 21

Neuropeptide Y (NPY) inhibits electrogenic Cl secretion in rat jejunal epithelium under voltage clamp conditions. This effect is dependent upon endogenous eicosanoid formation since it is blocked by the cyclooxygenase inhibitor, piroxicam, which itself has an inhibitory action upon chloride secretion. A number of chloride secretagogues have been examined for their ability to restore the antisecretory effects of NPY. Data presented here shows that NPY responsiveness is restored, in piroxicam pretreated tissues, by vasoactive intestinal polypeptide (VIP), forskolin, prostaglandin E2 (PGE2) isobutyl-1-methyl-xanthine (IBMX) and dibutyryl cAMP added prior to the neuropeptide. While all these agents cause chloride secretion by elevating intracellular cAMP, NPY is also effective in inhibiting the secretory effects of carbachol (CCh) and substance P (SP), agents believed to act by raising intracellular calcium (Cai). Although there is evidence that NPY can inhibit adenylate cyclase, its ability to attenuate chloride secretion brought about by secretagogues acting through both adenylate cyclase and calcium mechanisms, implies that NPY has either a more general fundamental mechanism or has multiple interactions with different second messenger systems.
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PMID:Neuropeptide Y antagonises secretagogue evoked chloride transport in rat jejunal epithelium. 246 61


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