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PubMed2000

Nitric oxide synthesis causes inositol phosphate production and Ca2+ release in rat parotid acinar cells.

The activity of nitric oxide synthase (NOS) in rat parotid acinar cells was measured using a newly synthesized fluorescent NO indicator DAF-2/DA. Our results show that NO production is most effectively stimulated by activation of the beta-adrenergic receptor, and to a minor extent by substance P (SP). NO activates the production of cGMP, an intracellular messenger that has been shown to release Ca2+ from ryanodine-sensitive intracellular stores. We found that cGMP is also able to release Ca2+ from ryanodine-insensitive intracellular stores. Our data show that a rise in the cGMP concentration induces inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] synthesis and Ca2+ release from intracellular stores.

Adrenergic beta-Agonists↗
PubMed1989

Effect of esters of succinic acid and other citric acid cycle intermediates on insulin release and inositol phosphate formation by pancreatic islets.

Esters of carboxylic acids are permeable to cells and once inside the cell are hydrolyzed to carboxylic acids. Methyl and ethyl esters of succinate and other citric acid cycle intermediates were tested to find out whether they are insulin secretagogues. Monomethyl succinate stimulated insulin release from pancreatic islets in a concentration-dependent manner with maximal release attained at a concentration of 10 mM. Dimethyl succinate (10 mM) was as effective as monomethyl succinate, but pyruvate methyl ester, monoethyl succinate, and dimethyl fumarate were ineffective as primary secretagogues. However, dimethyl fumarate potentiated both leucine- and leucine-plus-glutamine-induced insulin release. Glucose, leucine, leucine plus glutamine, and monomethyl succinate increased inositol tris-, bis- and monophosphate formation in pancreatic islets and antimycin A inhibited this formation. Since mitochondrial metabolism is probably essential for glucose-induced insulin release and the metabolism of succinate and leucine (without or with glutamine) involves mitochondrial respiration exclusively, these results might indicate that mitochondrial metabolism generates conditions or factors that are transmitted to the cytosol to increase inositol trisphosphate formation and thus calcium mobilization and insulin release. Since succinate is believed to enter metabolism at site II of the mitochondrial respiratory chain, it is interesting that rotenone, an inhibitor of NADH dehydrogenase and site I of the respiratory chain, was a potent inhibitor of monomethyl succinate-induced insulin released. Rotenone also inhibited leucine (plus or minus glutamine)-induced insulin release. These results indicate that beta cell metabolism of monomethyl succinate and leucine, like glucose, influences dehydrogenases that produce NADH.

Animals↗
PubMed1991

Hexadecylphosphocholine inhibits inositol phosphate formation and protein kinase C activity.

Hexadecylphosphocholine (HePC) inhibits protein kinase C (PKC) from NIH3T3 cells in cell-free extracts with a 50% inhibitory concentration of about 7 microM. Inhibition is competitive with regard to phosphatidylserine with a Ki of 0.59 microM. In order to determine whether HePC affects PKC in intact cells, the bombesin or tetradecanoylphorbolacetate-induced, PKC-mediated activation of the Na+/H(+)-antiporter was determined. It is demonstrated that HePC causes a drastic inhibition of this enzyme indicating a similar sensitivity of PKC to HePC in intact cells compared to cell-free extracts. In addition to the effects on PKC, treatment of NIH3T3 cells with HePC depresses the bombesin-induced formation of inositol 1,4,5-trisphosphate and the concomitant mobilization of intracellular Ca2+. Dose-response curves for the inhibition of inositol 1,4,5-trisphosphate formation and Ca2+ mobilization reveal 50% inhibitory concentrations of 2 or 5 microM, respectively. Polyphosphorylated phosphoinositides accumulate in HePC-treated cells indicating that the depression of inositol 1,4,5-trisphosphate generation is not caused by an inhibition of phosphoinositide kinases. Addition of bombesin to HePC-treated cells in the presence of LiCl revealed no evidence for an accelerated rate of inositol 1,4,5-trisphosphate turnover by the phospholipid analogue. It is concluded that HePC inhibits phosphoinositidase C in intact cells. The data strongly suggest that the growth-inhibitory effect of HePC is at least in part explained by the interference with mitogenic signal transduction.

Bombesin↗
PubMed2001

Inositol phosphates: Does IP(4) run a protection racket?

The phosphorylation of IP(3) by IP(3) 3-kinase leads to a number of physiological events, most of which are poorly understood. Recent findings about a hitherto unsuspected action of the IP(3) 3-kinase product, IP(4), suggest that the evolution of IP(3) 3-kinase may have even more far-reaching consequences than we thought.

Animals↗
PubMed2002

A novel Ala(-3)Thr mutation in the signal peptide of human luteinizing hormone beta-subunit: potentiation of the inositol phosphate signalling pathway and attenuation of the adenylate cyclase pathway by recombinant variant hormone.

Upon screening for polymorphisms in the human luteinizing hormone beta-subunit (LH beta) gene, we discovered a novel mutation in the LH beta signal peptide with functional consequences for signal transduction in mouse Leydig tumour cells (mLTC-1). This G(52)A point mutation in exon 2 of the LH beta gene, detected in heterozygous form in several normal DNA samples, caused an Ala(-3)Thr amino acid substitution. Recombinant forms of wild-type (WT) and Ala(-3)Thr variant (V) LH were produced in human embryonic kidney (HEK) 293 cells and purified. The immunoreactivities of the recombinant LH were determined by immunofluorometric assays and in-vitro bioactivities in mLTC-1 cells were assessed by using cAMP, progesterone and inositol trisphosphate (IP(3)), and activation of mitogen-activated protein kinase (MAPK) as end-points. Whereas both LH forms stimulated progesterone production and MAPK in similar fashion, WT-LH was more potent in stimulating cAMP, and V-LH was more potent in stimulating IP(3) generation. Both LH forms bound to LH receptors with similar affinities. No evidence was found for influence of the signal peptide mutation on efficacy of alpha- and beta-subunit dimerization. Sequencing of the recombinant V-LH beta protein also revealed that the mutation did not interfere with signal peptide cleavage. In summary, the present findings indicate that the Ala(-3)Thr mutation in the LH beta-subunit signal peptide has functional consequences, in the form of dissociation of stimulatory potency for different signal transduction pathways in vitro.

Adenylyl Cyclases↗
PubMed1988

Histamine-induced intracellular free Ca++, inositol phosphates and electrical changes in murine N1E-115 neuroblastoma cells.

Apparent intracellular free Ca++ concentration [(Ca++]i) was measured in differentiated N1E-115 neuroblastoma by microinjecting cells with aequorin (estimated intracellular concentration, 4 microM) and measuring light emission. Histamine produced a transient, dose-dependent increase in [Ca++]i. Pyrilamine blocked completely the response to histamine whereas cimetidine had no effect. Omitting Ca++ from the external medium reversibly blocked the response. As well as a rise in [Ca++]i, histamine caused a concomitant cell hyperpolarization that was not blocked by ouabain, low Cl-, tetraethylammonium chloride/tetradotoxin or metiamide but was blocked by apamin and pyrilamine. A secondary small depolarization caused by histamine was also blocked by apamin but not by ouabain, low Cl- or tetraethylammonium chloride/tetrodotoxin. Direct iontophoretic injection of Ca++ into cells caused only hyperpolarization. Injection of inositol 1,4,5-trisphosphate [IP3(1,4,5)] caused an increase in [Ca++]i and rapid hyperpolarization. Inositol 1,3,4-trisphosphate [IP3(1,3,4)] caused an increase in [Ca++]i, rapid hyperpolarization and a slower depolarization. Repeated injections of IP3(1,3,4) led to a diminished [Ca++]i response and decreased hyperpolarization but had no effect on depolarization. Inositol 1,3,4,5-tetrakisphosphate was without effect on [Ca++]i or on cellular membrane potential. The results suggest that histamine causes an H1 receptor-dependent increase in [Ca++]i, probably by the increased entry of extracellular Ca++, although there may be a contribution from intracellular Ca++ released by IP3(1,4,5). The increase in [Ca++]i activates K+ channels leading to cell hyperpolarization. IP3(1,3,4) formed from inositol 1,3,4,5-tetrakisphosphate, which is itself a product of IP3(1,4,5), causes a slower depolarization by a mechanism that does not involve Na+ channels or an increase in [Ca++]i.

Animals↗
PubMed1993

Prostaglandin F2 alpha stimulates inositol phosphate production in human pregnant myometrium.

We examined the effect of prostaglandin F2 alpha (PGF2 alpha) on phosphoinositide (PI)-hydrolysis in the outer layer of the human myometrium at the end of pregnancy. After pretreatment of myometrial explants with a cyclo-oxygenase inhibitor (indomethacin), the PGF2 alpha dose-response curve was shifted to the left and a maximal level of PGF2 alpha-induced IP accumulation was reached. In contrast, the well-known OT-induced IP accumulation was decreased in the presence of indomethacin, whereas potency was unchanged. Incubation of the myometrial explants with calcium-depleted medium, not only decreased the basal IP production but completely abolished the OT- and PGF2 alpha-induced IP accumulation. A L-type calcium channel inhibitor, verapamil 100 microM, significantly decreased PGF2 alpha-induced total inositol production whereas it had no effect on OT-response, suggesting that the first event of PGF2 alpha action is the activation of a calcium channel. These results point to marked differences in the mechanisms by which OT and PGF2 alpha exert their contractile effects in human myometrium at the end of pregnancy.

Calcium↗
PubMed1991

Ca2+ channel agonists enhance thyrotropin-releasing hormone-induced inositol phosphates and prolactin secretion.

The dihydropyridine Ca2+ channel activator BAY K 8644 (1 microM) stimulated basal prolactin secretion from perifused primary cultures of anterior pituitary cells and potentiated the stimulation of prolactin secretion by 1 microM thyrotropin-releasing hormone (TRH) 5-fold over 30 min. This potentiation was mimicked by other dihydropyridine agonists CGP 28392 and (+)-SDZ 202-791 and by (-)-BAY K 8644 (1 microM), but not by (+)-BAY K 8644. The Ca2+ channel antagonist nimodipine, at a concentration sufficient to block BAY K 8644-stimulated 45Ca2+ uptake in GH4C1 anterior pituitary tumor cells, decreased basal prolactin secretion and blocked the enhancement of basal and TRH-stimulated secretion by BAY K 8644. These results suggest that dihydropyridine agonists potentiate TRH-induced secretion through interaction with known stereospecific sites on Ca2+ channels. In GH4C1 cells, BAY K 8644 alone did not affect inositol polyphosphate accumulation, but potentiated TRH-stimulated accumulation of inositol 1,3,4-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Accumulation of the Ca(2+)-mobilizing isomer inositol 1,4,5-trisphosphate was not potentiated, suggesting that potentiation of TRH-stimulated hormone secretion by BAY K 8644 does not result from synergistic stimulation of phospholipase C, but may correlate with enhanced inositol trisphosphate-3-kinase activity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1995

Staurosporine inhibits inositol phosphate formation in bovine adrenal medullary cells.

The effect of protein kinase C activators and inhibitors on histamine-stimulated phospholipase C in bovine adrenal medullary cells has been investigated. The protein kinase C activators, phorbol 12,13-dibutyrate (PDB) or sn-1,2-dioctanoylglycerol (DOG), inhibited histamine-stimulation of phospholipase C. This inhibition was prevented by the protein kinase C-selective inhibitor Ro 31-8220 (3-[1-[3-(2-isothioureido) propyl]indol-3-yl]-4-(1-methylindol-3-yl)-3-pyrrolin-2,5-dio ne) but not the broad spectrum protein kinase inhibitor staurosporine. Indeed staurosporine on its own inhibited both the histamine-stimulated response and, in permeabilized cells, phospholipase C activated by Ca2+. Staurosporine inhibition of phospholipase C is unlikely to be mediated via protein kinase A or Ca2+/calmodulin-dependent protein kinase because it was not reproduced by selective inhibition of these kinases. Staurosporine treatment, however, reduced inositol phospholipid levels in stimulated cells. Thus staurosporine and Ro 31-8220, two widely used protein kinase C inhibitors, have quite different effects on phospholipase C activation. Furthermore, staurosporine may cause this inhibition through a reduction in the level of phospholipase C substrate.

Adrenal Medulla↗
PubMed1990

Regulation of calcium influx across the plasma membrane of the human T-leukemic cell line, JURKAT: dependence on a rise in cytosolic free calcium can be dissociated from formation of inositol phosphates.

A rise in the cytosolic free Ca2+ concentration due to both mobilization of Ca2+ from internal stores and influx of extracellular Ca2+ across the plasma membrane through 'second messenger-operated Ca2+ channels' is one of the first transmembrane signals detected following activation of CD2 or CD3 receptors on T-cells. In this study, we have further elucidated the regulation of these channels in the human T-leukemic cell line, JURKAT. Stimulation with either OKT3 or PHA induced a prompt influx of Ca2+ as assessed by MN2+ quenching of intracellular fura-2 fluorescence. When cytosolic free Ca2+ transient was partially buffered by loading the cells with BAPTA, neither agonist could induce Ca2+ entry into the cells as depicted by the lack of quenching of the fluorescence signal by Mn2+. This is in good agreement with our previous data on agonist-induced 45Ca2+ influx demonstrating that a rise in cytosolic free Ca2+ due to agonist-induced mobilization of Ca2+ from intracellular stores, could, directly or indirectly via the inositol cycle, initiate Ca2+ influx in these cells. Further support of this idea comes from the data demonstrating that agonist-induced mobilization of Ca2+ precedes the influx of Ca2+ across the plasma membrane. The present findings show that agonist-stimulation significantly increased the levels of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 after only 5 s, indicating that one or both of these substances could play a role in the regulation of Ca2+ influx. However, when agonist-induced Mn2+ influx was totally abolished, by partially buffering the cytosolic free Ca2+ rise, the formation of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 was not affected. Consequently, the dependence of an initial rise in cytosolic free Ca2+ for the subsequent regulation of Ca2+ influx across the plasma membrane, can be dissociated from the formation of both Ins(1,4,5)P3 and Ins(1,3,4,5)P4.

Aminoquinolines↗
PubMed1986

Two species of phospholipase C isolated from lymphocytes produce specific ratios of inositol phosphate products.

Chromatography of the soluble porcine lymphocyte phospholipase C on cellulose phosphate resolves the activity into two species. An HPLC method is described for separating the enzyme products, Ins 1,2 greater than P and Ins 1P. Use of these methods reveals that the two iso-enzymes liberate, with a high degree of reproducibility, characteristic ratios of the two products. This suggests that the amount of each product produced is an inherent property of the enzyme mechanism.

Animals↗
PubMed1987

Inositol phosphate formation and chloride current responses induced by acetylcholine and serotonin through GTP-binding proteins in Xenopus oocyte after injection of rat brain messenger RNA.

The molecular mechanism underlying the signal transduction from muscarinic and serotonergic receptors to Cl- channels were investigated in Xenopus oocyte microinjected with rat brain poly(A)+ mRNA. Transient Cl- current responses of the mRNA-injected oocytes to acetylcholine (ACh) and serotonin (5-HT) were similar in amplitude and onset. Although pharmacological characterization indicated that distinct M1-like and S1-like receptors of rat brain are involved in the ACh and 5-HT responses, respectively, these responses cross-desensitized each other completely. A common involvement of the GTP-binding proteins coupled to phosphoinositide breakdown was suggested by the findings that intracellular application of guanosine 5'-O-(2-thio)bisphosphate (GDP beta S) or neomycin greatly suppressed both ACh and 5-HT responses. These responses were not affected by exposure of the mRNA-injected cells to cholera toxin, but they were inhibited by pertussis toxin. The increase in inositol trisphosphate (IP3) responsive both to ACh and 5-HT coincided with the expression of Cl- current responses. However, only 5-HT but not ACh slightly increased the cyclic AMP (cAMP) content of the mRNA-injected cells. Intracellular injection of either IP3 or Ca2+ produced a transient Cl- current in the mRNA-injected cells as well as in non-injected cells, while 1-oleoyl-2-acetylglycerol (OAG), cAMP or cyclic GMP (cGMP) never elicited chloride current responses. It was proposed that muscarinic and serotonergic receptors are commonly linked to phosphoinositide breakdown through the mediation of GTP-binding proteins Ni and/or No in mRNA-injected oocytes.

Acetylcholine↗
PubMed1990

Expression of striatal D1 dopamine receptors coupled to inositol phosphate production and Ca2+ mobilization in Xenopus oocytes.

Expression of central nervous system receptors for dopamine was examined by injection of poly(A)+ RNA (mRNA) from rat striatum into oocytes from Xenopus laevis. Electrophysiological measurements in mRNA-injected oocytes indicated that addition of 100 microM dopamine induced an inward current (40-100 nA) that was consistent with the activation of endogenous Ca2(+)-dependent Cl- channels. This current was also elicited by addition of the selective D1 agonist SKF 38393 but not by the selective D2 agonist quinpirole. Prior addition of the dopaminergic antagonist cis-piflutixol completely abolished dopamine-induced currents but had no effect on currents produced by serotonin. Using 45Ca2+ efflux assays, addition of 100 microM dopamine to injected oocytes stimulated efflux 2- to 3-fold. This increase was mimicked by SKF 38393 and was blocked by the D1-selective antagonist (+)SCH 23390 but not by the D2-selective antagonist domperidone. No increase in 45Ca2+ efflux was seen with 100 microM quinpirole. Size fractionation of striatal mRNA yielded a single peak (2.5-3.0 kilobases) of D1 receptor-mediated 45Ca2+ efflux activity in injected oocytes. In addition, dopamine stimulation of oocytes injected with peak fractions and prelabeled with myo-[3H]inositol caused a 3-fold increase in [3H]inositol 1,4,5-triphosphate [( 3H]InsP3) formation. No effect on [3H]InsP3 production or 45Ca2+ efflux was observed, however, in injected oocytes incubated with 1 mM N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate. Thus, in addition to D1 receptors that stimulate adenylyl cyclase, rat striatum contains D1 receptors that can couple to InsP3 formation and mobilization of intracellular Ca2+.

Animals↗
PubMed1993

Arginine vasopressin-induced sensitization in brain: facilitated inositol phosphate production without changes in receptor number.

Arginine vasopressin (AVP) has been shown to have a unique sensitization effect whereby repeated injection of AVP into a lateral cerebral ventricle or a mediobasal region of the rat forebrain below the lateral septum and including the anterior hypothalamus referred to as the ventral septal area, causes enhanced motor responses to the ligand. To elucidate possible neuronal mechanisms responsible for AVP sensitization, 1) we determined the dose and the time required for the development and expression of AVP sensitization, and 2) we tested the hypotheses that AVP sensitization may result in a) alteration of septal AVP V1 receptor affinity or number, and/or b) alteration of septal AVP V1 receptor signal transduction (phosphatidylinositol hydrolysis) mechanisms. Our behavioral data show that the magnitude of AVP sensitization varies with dose and time, and the effect is dependent on the time interval between injections, in that an initial intracerebroventricular AVP injection enhances the sensitivity of the animals to the motor effects of similar AVP injections given 6 h to 6 days later but not to injections given hourly or weekly. No changes in septal AVP binding site density and affinity, as measured by [3H]AVP binding to septal synaptic plasma membrane, were found in sensitized animals; [3H]inositol monophosphate stimulation in response to AVP in septal slices, however, was found to be significantly enhanced. This enhanced [3H]inositol monophosphate stimulation appears specific to a V1-type receptor because it was significantly reduced in the presence of the V1 receptor antagonist, d(CH2)5Tyr(Me)AVP, and was not found using oxytocin or the V2 receptor agonist, DDAVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Inhibition of hormone-stimulated inositol phosphate production and disruption of cytoskeletal structure. Effects of okadaic acid, microcystin, chlorpromazine, W7 and nystatin.

Inhibition of protein phosphatases 2A and 1 by okadaic acid and microcystin leads to cytoskeletal disruption and formation of plasma membrane blebs (blebbing) in hepatocytes. This phenomenon is associated to a marked inhibition of receptor-mediated and G-protein-mediated phosphoinositide turnover in rat hepatocytes. Other cytoskeletal-disrupting drugs such as chlorpromazine, W7 and nystatin mimic the effect of these protein phosphatase inhibitors on phosphoinositide metabolism and blebbing. Our data suggest that the coupling between G-protein and phospholipase C might be altered by cytoskeletal disruption.

Animals↗
PubMed1991

Role of eicosanoids, inositol phosphates and extracellular Ca2+ in cell-volume regulation of rat liver.

1. In isolated perfused rat liver, the time-course of volume-regulatory K+ efflux following exposure to hypoosmolar perfusate resembled the leukotriene-C4-induced K+ efflux in normotonic perfusion. Omission of Ca2+ from the perfusion fluid had no effect on volume-regulatory K+ efflux, but abolished completely the leukotriene-C4-induced K+ efflux. 2. Volume-regulatory K+ fluxes following hypoosmolar exposure (225 mOsmol l-1) and subsequent reexposure to normotonic media (305 mOsmol l-1) were not significantly affected by the cyclooxygenase inhibitors indomethacin (5 mumol l-1) or ibuprofen (50 mumol l-1), the leukotriene D4/C4-receptor antagonist 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]etha none (YL 171883, 50 microM), the lipoxygenase inhibitor nordihydroguaiaretic acid (20 microM), the phospholipase-A2 inhibitor bromophenacyl bromide (50 microM) or the thromboxane-receptor antagonist 4-[2-(benzenesulfonamido)ethyl]-phenoxyacetic acid (BM 13.177, 20 microM). Also the effects of hypoosmotic cell swelling on lactate, pyruvate and glucose balance across the liver remained largely unaffected in presence of these inhibitors. Neither exposure of perfused rat liver to hypoosmolar (225 mOsmol l-1) nor to hyperosmolar (385 mOsmol l-1) perfusion media affected hepatic prostaglandin-D2 release. 3. When livers were 3H-labeled in vivo by an intraperitoneal injection of myo-[2-3H]inositol about 16 h prior to the perfusion experiment, cell swelling due to lowering the perfusate osmolarity from 305 mOsmol l-1 to 225 mOsmol l-1 led to about a threefold stimulation of [3H]inositol release. The maximum of hypotonicity-induced [3H]inositol release preceded maximal volume-regulatory K+ efflux by about 30 s, but came after the maximum of water shift into the cells. Hypotonicity-induced [3H]inositol release was largely prevented in presence of Li+ (10 mM), but simultaneously inositol monophosphate accumulated inside the liver within 10 min and a small, but significant increase of inositol trisphosphate 1 min after onset of hypoosmolar exposure was detectable. No stimulation of [3H]inositol release was observed during cell shrinkage by switching the perfusate osmolarity from 225 mOsmol l-1 to 305 mOsmol l-1 or from 305 mOsmol l-1 to 385 mOsmol l-1. No stimulation of [3H]inositol release was observed upon swelling of preshrunken livers by lowering the osmolarity from 385 mOsmol l-1 to 305 mOsmol l-1, although the volume-regulatory K+ efflux under these conditions was almost identical to that observed after lowering the osmolarity from 305 mOsmol l-1 to 225 mOsmol l-1. 4.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

[Extracellular ATP evoked catecholamine release and inositol phosphates formation in cultured porcine adrenal medullary cells].

ATP is ubiquitously present in neural tissues and is released during nerve stimulation. It is known that splanchnic nerve terminals located in adrenal medulla also contain acetylcholine and ATP. These substances may be released concomitantly with nerve stimulation. ATP can exert its effects on neuron-effector junctions by acting directly as a neurotransmitter by increasing or decreasing the release of other neurotransmitters or by modulating their actions. Chern et al. reported that ATP and adenosine inhibited acetylcholine stimulated secretion of catecholamine from isolated bovine adrenal medullary cells. However, Kim et al. showed that extracellular ATP stimulated catecholamine secretion from cultured bovine adrenal medullary cells. Therefore, we investigated the effect of ATP on second messengers levels in cultured porcine adrenal medullary cells as well as catecholamine release from the cells. ATP (500 microM-5mM) evoked catecholamine release significantly (p < 0.05). An unhydrolyzable ATP analogue, ATP gamma S, was several times more potent than ATP in the secretion. ATP-evoked maximal secretion of catecholamine was several times less potent than that evoked by carbachol. Removal of extracellular Ca2+ did not effectively inhibit ATP-induced secretion. 45Ca2+ influx was not observed by the addition of ATP. These results indicated that the catecholamine secretion induced by ATP was independent of extracellular Ca2+. ATP evoked cAMP production slightly at 1mM and did not affect cGMP content. On the other hand, ATP (100 microM-5mM) induced a remarkable increase in inositol trisphosphate, a messenger for mobilization of Ca2+ from intracellular storage sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1989

Differential mechanisms of inositol phosphate generation at the receptors for bombesin and platelet-derived growth factor.

We investigated the mechanism(s) whereby activation of a growth-factor receptor typically endowed with tyrosine kinase activity, such as the platelet-derived growth factor (PDGF) receptor, triggers phosphoinositide hydrolysis. In Swiss 3T3 cells permeabilized with streptolysin O, an analogue of GTP, guanosine 5'-[gamma-thio]triphosphate, was found to potentiate the coupling of the bombesin receptor to phospholipase C. In contrast, the activation of the enzyme by PDGF occurred in a GTP-independent manner. Moreover, the inactive analogue of GTP, guanosine 5'-[beta-thio]diphosphate, significantly inhibited the bombesin-induced InsP3 generation, whereas it did not decrease the same effect when stimulated by PDGF.

Animals↗