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)

A transient decrease in cytosolic pH ([pH]i) in rat parotid cells was evoked by the addition of carbachol (CCh), phenylephrine, or substance P, whereas isoproterenol and dibutyryl cyclic AMP had little or no effect on [pH]i. The decrease in [pH]i induced by the Ca(2+)-mobilizing agonists was also observed in Ca(2+)-free medium, but not when the intracellular Ca2+ stores were previously depleted. Ionomycin and thapsigargin elicited a decrease in [pH]i with an increase in cytosolic Ca2+ concentration ([Ca2+]i). The protein kinase C activator and inhibitor had no effect on the agonist-induced decrease in [pH]i. These results suggest that the cytosolic acidification is associated with an increase in [Ca2+]i.
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PMID:The cytosolic acidification in rat parotid cells is associated with an increase in cytosolic Ca2+ concentration. 832 Aug 81

Ductal elements within salivary glands are responsible for modifying the electrolyte composition of primary saliva secreted by the acini. To study the mechanism and regulation of the transport processes involved requires a suitable preparation of functional ducts. To this end we have isolated intralobular ducts from rabbit mandibular salivary glands using the technique of tissue dissociation and microdissection. Light and electron microscopy demonstrated that the ducts corresponded ultrastructurally to striated intralobular ducts of the intact gland. Ducts could be maintained in tissue culture on polycarbonate filter rafts for up to 36 h, during which time the ends of the ducts did not usually seal. The overall resting content of ductal adenosine 3',5'-cyclic monophosphate (cyclic AMP) was 16.0 +/- 3.0 fmol mm-1 and increased dose dependently in response to stimulation with the beta-adrenoceptor agonist isoprenaline (10(-9)-10(-4) M; concentration required to produce a half-maximal response, K0.5 = 2.1 x 10(-6) M). The response to isoprenaline was blocked by the antagonist propranolol. Intracellular cyclic AMP content was also raised by the adenylate cyclase activator forskolin and by prostaglandin E2. Acetylcholine (3 x 10(-8)-10(-5) M) caused a dose-dependent and maintained rise in [Ca2+]i (K0.5 = 2.5 x 10(-7) M). This increase in [Ca2+]i could be reversed by the muscarinic antagonist atropine and appeared to result from a combination of mobilization of intracellular Ca2+ stores and entry of Ca2+ from the extracellular fluid. Noradrenaline induced only a very small, mainly transient rise in [Ca2+]i while phenylephrine failed to increase [Ca2+]i at all. Vasoactive intestinal peptide (5 x 10(-7) M) also produced a marginal, maintained rise in [Ca2+]i. Substance P, bombesin, isoprenaline, and prostaglandin E2 did not elevate [Ca2+]i. Application of the calcium ionophore ionomycin induced a substantial maintained rise in [Ca2+]i. Taken together, these results indicate that isolated and cultured striated ducts (i) possess intact beta-adrenoceptors coupled to adenylate cyclase, putative receptors for prostaglandin E2 and muscarinic receptors, and (ii) represent a viable preparation for the study of the transport mechanisms involved in the ductal modification of salivary fluid composition.
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PMID:Structural and functional characterization of striated ducts isolated from the rabbit mandibular salivary gland. 838 3

The bovine neurokinin-2 (NK-2) receptor gene was stably transfected into Baby hamster kidney (BHK-21) fibroblasts and one recombinant clone expressing 17,700 high-affinity [125I]neurokinin A (NKA) binding sites/cell characterized further. [125I]NKA binding was displaced by unlabeled NKA with an IC50 of 8.26 +/- 2 nM (n = 5) and with the rank order of potency NKA > neurokinin B (NKB) > Substance P (SP) confirming pharmacological characteristics of an NK-2 receptor subtype. Stimulation with NKA resulted in a rapid and dose-dependent increase in inositol 1,4,5-trisphosphate (IP3) levels (EC50 = 32 +/- 10 nM; n = 7) which was paralleled by a transient biphasic rise in intracellular free calcium concentration [Ca2+]i (EC50 = 35 +/- 20 nM; n = 3). In addition to phosphoinositide (PI) hydrolysis and Ca2+ mobilization, NKA was found to stimulate both cyclic AMP formation (EC50 = 1.02 +/- 0.26 microM; n = 7) and [3H]arachidonic acid mobilization (EC50 = 0.65 +/- 0.45 microM; n = 4). Interestingly, cyclic AMP levels also rose after addition of an exogenous arachidonic acid metabolite, prostaglandin E2 (PGE2) (EC50 = 11.5 +/- 2 microM). Similar observations of NKA-induced IP3 production, Ca2+ mobilization, arachidonic acid liberation, and cAMP formation have been made previously following expression of the bovine NK-2 receptor in Chinese hamster ovary (CHO) epithelial cells. The present results suggest that activation of NK-2 receptors leads to characteristic and reproducible intracellular second messenger responses in a subclass of cell types which includes fibroblasts and epithelial cells irrespective of their genetic and phenotypic background.
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PMID:Signal transduction mechanisms of recombinant bovine neurokinin-2 receptor stably expressed in baby hamster kidney cells. 839 39

In C6-2B cells, agonist-stimulated cyclic AMP accumulation is inhibited when the cytosolic Ca2+ concentration is increased. We now demonstrate that in C6-2B cells: (i) the early kinetics of the cyclic AMP inhibition by substance K (t1/2 = 35 s) and thapsigargin (t1/2 = 1.6 min) closely mimic the kinetics of the cytosolic Ca2+ increase evoked by either agent (t1/2 = 25 s and 1.5 min respectively); (ii) the Ca2+ rise and cyclic AMP inhibition by substance K or thapsigargin are similarly affected in EGTA-containing medium; (iii) PCR detects type-III and type-VI adenylate cyclase cDNAs, and RNAase protection assays show that the mRNA for type-VI adenylate cyclase, an isoform inhibitable by submicromolar Ca2+ concentrations, is the predominant species, strongly suggesting that type-VI adenylate cyclase is probably the target molecule for Ca(2+)-mediated inhibition of cyclic AMP accumulation.
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PMID:Predominant expression of type-VI adenylate cyclase in C6-2B rat glioma cells may account for inhibition of cyclic AMP accumulation by calcium. 839 57

[3H]Inositol phosphate responses to histamine and a range of other agonists were studied in cultured human tracheal smooth muscle cells. Histamine (EC50 6.5 microM), bradykinin (EC50 9.7 nM), carbachol (EC50 10 microM), substance P and NaF all produced concentration dependent [3H]inositol phosphate formation in these cells. The response to histamine was inhibited by mepyramine (KA 4.3 x 10(9) M-1), indicating the involvement of the histamine H1 receptor in this response. The inositol phosphate response to histamine was apparently desensitized following prolonged agonist exposure. The response to histamine was inhibited by phorbol dibutyrate (IC50 6 nM), and this inhibitory effect was reversed by staurosporine (150 nM). Isoprenaline (1 microM), rolipram (0.1-100 microM) and 3-isobutyl-1-methylxanthine (0.1 mM) all produced small inhibitory effects upon histamine induced inositol phosphate formation. These results demonstrate that cultured human tracheal smooth muscle cells express histamine H1 receptors coupled to phosphoinositidase C and suggest that the inositol phosphate response induced by stimulation of this receptor subtype is inhibited by activation of protein kinase C and, to a lesser extent, by elevation of cell cyclic AMP content.
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PMID:Control of histamine induced inositol phospholipid hydrolysis in cultured human tracheal smooth muscle cells. 839 92

To examine the mechanisms of an angiotensin-converting enzyme (ACE) inhibitor-induced cough in perimenopausal and postmenopausal women, cough responses to aerosols of capsaicin and citric acid were examined in four groups of female guinea pigs treated orally with danazol (D) (an agent decreasing plasma estrogen levels), cilazapril (C) (an inhibitor of ACE), both danazol and cilazapril (C+D), or without either drug (control group) for 4 to 5 wk. Capsaicin caused dose-dependent increases in the number of coughs in all four groups. C or D alone shifted dose-response curves to capsaicin (from 10(-7) M to 10(-3) M) to lower concentrations compared with the control, and C+D further shifted them. Likewise, the number of coughs induced by citric acid (3 x 10(-1) M; 2 min) was highest in animals treated with C+D and significantly higher in animals treated with C or D than in the control group. Aerosols of a selective substance P (SP) receptor antagonist FK 888 (10(-5) M; 2 min) inhibited capsaicin-induced cough in all four groups, and dose-response curves to capsaicin did not differ significantly at any concentrations among the four groups in the presence of FK 888 (p > 0.10). D decreased cyclic AMP levels in the trachea, irrespective of the combination of C. A beta 2-adrenoceptor agonist, procaterol, which is thought to inhibit SP release by elevation of cyclic AMP in sensory nerves, dose-dependently inhibited the number of coughs induced by capsaicin (10(-3) M) in animals treated with D. The present study suggests that SP is a common mechanism mediating increases in the sensitivity of cough reflex induced by both ACE inhibition and a decrease in plasma estrogen levels, and the additive effects of the two events may explain the high incidence of cough during ACE inhibitor therapy in perimenopausal and postmenopausal women.
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PMID:Angiotensin-converting enzyme inhibitor and danazol increase sensitivity of cough reflex in female guinea pigs. 856 37

Pancreatic duct bicarbonate secretion is mediated primarily by secretin-induced elevation of intracellular cyclic AMP, although little is known of the effects of other physiological regulators on pancreatic duct cyclic AMP metabolism. We investigated the effects of secretin and several other potential agonists on cyclic AMP levels in isolated guinea pig main and interlobular pancreatic duct segments and in cultured duct epithelial monolayers. Secretin (0.1 microM) caused a five- to eightfold elevation of cyclic AMP in both isolated ducts and cultured monolayers (EC50 = 0.15 nM). Main duct segments, while responsive, were less so than segments of interlobular duct. In isolated duct segments, carbachol, bombesin, cholecystokinin, substance P, calcitonin gene-related peptide, glucagon, insulin, isoproterenol, neurotensin, and prostaglandin E2 did not significantly alter resting or secretin-stimulated cyclic AMP levels. In contrast, 0.1 microM vasoactive intestinal peptide significantly increased cyclic AMP to a level comparable to that evoked by an equal concentration of secretin. Somatostatin significantly attenuated the effects of a submaximal (physiological) dose of secretin on duct cyclic AMP levels without altering resting cyclic AMP levels, suggesting that somatostatin's effects on pancreatic duct fluid secretion are mediated by inhibition of adenylyl cyclase activity.
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PMID:Regulation of cyclic AMP levels in guinea pig pancreatic ducts and cultured duct epithelial monolayers. 857 80

Calcium signaling in fura-2 acetoxymethyl ester-loaded enteric glia was investigated in response to neuroligands; responses to ATP were studied in detail. Carbachol (1 mM), glutamate (100 microM), norepinephrine (10 microM), and substance P (1 microM) did not increase the intracellular calcium concentration ([Ca2+]i) in cultured enteric glia. An increasing percentage of glia responded to serotonin (4%; 100 microM), bradykinin (11%; 10 microM), and histamine (31%; 100 microM), whereas 100% of glia responded to ATP (100 microM). ATP-evoked calcium signaling was concentration dependent in terms of the percentage of glia responding and the peak [Ca2+]i achieved; responses were pertussis toxin insensitive. Based on responsiveness of enteric glia to purinergic agonists and peak [Ca2+]i evoked, ATP = UTP > ADP > beta, gamma-methyleneadenosine 5'-triphosphate >> 2-methylthioadenosine 5'-triphosphate = alpha,beta-methyleneadenosine 5'-triphosphate = AMP = adenosine, suggesting a glial P2U receptor. Depletion of D-myo-inositol 1,4,5-trisphosphate-sensitive calcium stores by thapsigargin (10 microM) abolished glial responses to ATP. Similarly, calcium responses were decreased 92% by U-73122 (10 microM), an inhibitor of phospholipase C, and 93% by the phorbol ester phorbol 12-myristate 13-acetate (100 nM), an activator of protein kinase C. Thus, cultured enteric glia can respond to neurotransmitters with increases in [Ca2+]i. Our data suggest that glial responses to ATP are mediated by a P2U receptor coupled to activation of phospholipase C and release of intracellular calcium stores.
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PMID:Enteric glia exhibit P2U receptors that increase cytosolic calcium by a phospholipase C-dependent mechanism. 859 30

Calcitonin gene-related peptide (CGRP) and Substance P (SP) -immunoreactive nerves have been found in the anterior uvea of various mammalian species. Although SP is known to play a major role in control of pupil motility in rabbits, little is known about the effect of CGRP on the iris smooth muscles. We isolated iris sphincter and dilator muscles from rabbit eyes and investigated the mechanical responses and intracellular cyclic AMP (cAMP) levels in these muscles. CGRP (up to 0.1 microM) had no effect on either the resting muscle tone or the amplitude of contraction evoked by field stimulation of the sphincter. On the other hand, CGRP (0.1 microM) relaxed dilator muscle which had been pre-contracted by phenylephrine and reduced the amplitude of contraction evoked by field stimulation. These responses were antagonized by CGRP (8-37), a CGRP antagonist. The phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), dose-dependently inhibited the contraction evoked by field stimulation. However, 3 microM IBMX had no effect on CGRP inhibition of twitch contraction in this preparation. CGRP had little effect on cAMP production in dilator muscle either with or without IBMX. In conclusion, the miosis which occurs during an ocular inflammatory response, when both CGRP and SP are thought to be released from terminals of sensory neurons, results from CGRP relaxation of the dilator and from the strong contractile effect of SP on the sphincter. Adenylate cyclase activation does not seem to be involved in the relaxant effect of CGRP on the dilator.
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PMID:Calcitonin gene-related peptide induced relaxation of the rabbit iris dilator muscle. 863 Nov 97

The human NK-1 receptor transfected in Chinese hamster ovary (CHO) cells was studied with use of different tachykinin analogs: Substance P, [Pro9]SP, [Sar9, Met(O2)11]SP, [Gly9 psi (CH2CH2) Leu10]SP, Ac-Arg-septide, septide, [Gly9 psi (CH2CH2) Gly10]SP, NKA, [pGlu6]SP(6-11) and [Lys5]NKA(4-10). Binding experiments with [3H][Pro9]SP discriminated two classes of peptides with either high affinity (K iota in the nanomolar range) for the human NK-1 receptor or with low affinity (K iota in the micromolar range); this second group of peptides included NKA and [pGlu6]SP(6-11). In spite of these differences, both peptide families evoked potent stimulation of phosphatidylinositol hydrolysis (EC50 in the nanomolar range). In contrast, only NK-1 agonists, with high affinity, stimulated with great potency cyclic AMP formation (EC50 from 8 to 50 nM), whereas the second family of peptides were only weak agonists (EC50 in the micromolar range). RP 67580, CP 96345 and GR 94800, a NK-2 antagonist, were either competitive or uncompetitive inhibitors of inositol phosphates or cyclic AMP formations induced by [Pro9]SP, septide or NKA, independently of the agonist or the response studied. Thus, NKA, the presumed NK-2 endogenous peptide that may be co-released with SP, and the enzymatically produced C-terminal fragment of SP, [pGlu6]SP(6-11), may trigger specific pharmacological responses via the NK-1 receptor, at nanomolar concentrations, and thus regulate the action of SP at the NK-1 receptor.
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PMID:Tachykinin peptides affect differently the second messenger pathways after binding to CHO-expressed human NK-1 receptors. 878 33


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