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PubMed1990

Pertussis toxin inhibits norepinephrine-stimulated inositol phosphate formation in primary brain cell cultures.

Norepinephrine (NE) increased formation of [3H]inositol phosphates ( [3H]InsPs) in primary cultures of neuronal and glial cells from 1-day-old rat brain. This response appeared to be mediated by alpha 1-adrenergic receptors, because prazosin was 40-fold more potent than yohimbine in blocking it. Pretreatment with pertussis toxin (PTX) dose-dependently decreased this response by 70-80%. The IC50 for PTX (7 ng/ml) was similar to that for blocking of alpha 2-adrenergic receptor-mediated decreases in cyclic AMP accumulation in the same cells. PTX pretreatment caused only a small, not statistically significant, inhibition of the [3H]InsP response to the muscarinic cholinergic receptor agonist carbachol in these cells. Radioligand binding studies showed that both neuronal and glial cultures contained mixed populations of alpha 1a- and alpha 1b-adrenergic receptor subtypes. Selective inactivation of the alpha 1b population by chloroethylclonidine reduced NE-stimulated [3H]InsP formation by 25 +/- 6%. Pretreatment with both PTX and chloroethylclonidine caused additive decreases (90 +/- 3%) in the NE response. NE-stimulated [3H]InsP formation was partially dependent on extracellular calcium, because it was decreased 64 +/- 6% by removal of calcium and 56 +/- 13% by addition of 1 mM CdCl2, although it was not affected by 1 microM nifedipine. These results suggest that NE stimulates [3H]InsP formation in neuronal and glial cultures through a pertussis toxin-sensitive guanine nucleotide-binding protein. This response appears to be mediated primarily by the alpha 1a subtype and may be subsequent to calcium influx.

Animals↗
PubMed1992

Activation of muscarinic cholinergic receptors stimulates inositol phosphates synthesis in the developing avian cochlear duct.

We previously reported that the inositol phosphates (IPs) synthesis is induced by muscarinic agonists in the rat cochlea and that this stimulation is maximal at postnatal day 12. This peak response is concomitant with the onset of the efferent synaptogenesis at the outer hair cell level. Whether the correlation between this neuronal plasticity and the enhanced IPs formation is unique to the rat or a general feature of the developing vertebrate cochlea is not known. To examine this question, we measured, in the presence of LiCl, the accumulation of (3H)-IPs induced by carbachol, in the developing chick cochlear duct during a period ranging from embryonic day (E) 8 to post-hatching day (P) 20. Carbachol (1 mM) causes a significant increase of IPs formation relative to basal values at all ages. This IPs accumulation is maximal at E8 (1854% of the basal level), then, rapidly decreases until P13 when it reaches a steady-state level of 294% of the basal level. Strikingly, this gradual decline in IPs formation is interrupted between E15 and E19, by a transient increase in IPs synthesis. This rise peaks at E16 with a stimulation value of 757% of the control level. This maximal stimulation is inhibited by atropine in a dose-dependent manner, as is the case at E9, suggesting the involvement of muscarinic receptors. Interestingly, the occurrence of the peak response is concomitant with the plastic events associated with the maturation of the efferent innervation of the cochlear duct. Thus, these results suggest that there may be a correlation between cochlear plasticity and enhanced IPs synthesis, which is not species-specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia.

Recent studies have shown a significant increase of inositol phosphates (IPs) in skeletal muscle during episodes of halothane-induced malignant hyperthermia (MH) in pigs. After treatment with dantrolene and disappearance of MH crisis the IP concentrations returned to basal levels. In order to examine if the increase of IPs during halothane-induced MH may be related to an enhanced IP synthesis in response to activation of 5-HT2 (5-hydroxytryptamine) receptors, the effects of ritanserin, a selective 5-HT2 receptor antagonist, on IP levels were investigated. Biopsies of skeletal muscle of the hindlimbs were obtained in random order and IPs were determined in homozygous MH-susceptible (MHS) and MH-non-susceptible (MHN) swine in the following order: (1) basal, (2) after treatment with ritanserin (2.0 mg/kg), (3) after halothane challenge (3 vol% for 20 min). Basal concentrations of all IPs were higher in MHS than in MHN swine. Ritanserin did not cause any significant changes of IP levels compared to the basal concentrations in MHS and MHN pigs. In MHS pigs, ritanserin did not prevent a halothane-induced MH-crisis. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 levels were increased in MHS (during MH crisis) vs. basal concentrations, whereas no changes were found in MHN pigs. Since the increases of IP levels in MHS pigs during MH crisis found in the present study were comparable to those without pretreatment with ritanserin, shown by recent studies, it may be concluded that ritanserin does not prevent the increase of IPs during a halothane-induced MH. Thus, the present data indicate that increases of IP levels during halothane-induced MH in swine are due to other mechanisms than 5-HT mediated enhancement of IP synthesis.

Anesthetics, Inhalation↗
PubMed2003

Delta-opioid agonist-stimulated inositol phosphate formation in isolated, rabbit iris-ciliary bodies: role of G(i/o) proteins and Gbetagamma-subunits.

Our laboratory has previously demonstrated the ability of kappa- and delta-opioid agonists to decrease aqueous flow rates and intraocular pressure of rabbits. The mechanisms by which these agents act in the ciliary body of the rabbit could involve inhibition of cAMP production, as well as increased generation of inositol phosphates (IPs). With regard to enhanced production of IPs, it has been suggested that their levels can be augmented by stimulation of phospholipase C via opioid receptors linked to either Galpha-subunits derived from Gq proteins or Gbetagamma-subunits derived from G(i/o)-proteins. The aim of the current study is to investigate the role of pertussis toxin (PTX)-sensitive G-proteins and Gbetagamma-subunits in delta-opioid agonist-mediated changes in IP production in the isolated, rabbit iris-ciliary body (ICB). In one set of experiments, ICB segments were treated with the delta agonist, SNC80 (10(-12)-10(-7) mol/l) alone. Other experiments were conducted utilizing SNC80 following pretreatment with either phosducin (Gbetagamma-subunit scavenger), PTX, or the delta antagonist, naltrindole. IP production was measured by ion exchange chromatography. Basal levels of IPs in the rabbit ICB were 58,287 +/- 2162, 15,218 +/- 969 and 2083 +/- 367 dpm/mg protein for IP1, IP2 and IP3, respectively. The highly selective delta-opioid receptor agonist, SNC80, produced concentration-dependent increases in the levels of the IPs in the ICB, which were diminished in the presence of the delta antagonist, naltrindole, indicating the effect was mediated via activation of delta-opioid receptors. Pretreatment of tissues with PTX (75 ng/ml), completely abolished the concentration-dependent production of IPs generated by SNC80 (10(-11)-10(-7) mol/l). In addition, pretreatment with phosducin (1 nmol/l) ablated the SNC80 (1 nmol/l)-induced increase in the formation of all three inositol phosphates. Results from this study indicate that the delta-opioid receptor-mediated increase in IP production is a PTX-sensitive G(i/o) response that involves participation of Gbetagamma-subunits. Thus, delta-opioid receptor activation by SNC80 in the ICB could be responsible, in part, for suppression of aqueous humor dynamics.

Animals↗
PubMed1990

Ca2+ influx in human T lymphocytes is induced independently of inositol phosphate production by mobilization of intracellular Ca2+ stores. A study with the Ca2+ endoplasmic reticulum-ATPase inhibitor thapsigargin.

Thapsigargin (TG), a sesquiterpene lactone and non-phorbol 12-myristate 13-acetate tumor promoter, stimulates a rapid increase in intracellular free Ca2+ [( Ca2+]i) in human T lymphocytes clone P28. The [Ca2+]i response to TG is sustained in the presence of 1 mM extracellular Ca2+, while it becomes transient in Ca2(+)-free medium suggesting that TG activates both the release of Ca2+ from intracellular stores and the entry of Ca2+ from extracellular spaces. TG-induced Ca2+ influx is completely abolished after cell depolarization caused by increased extracellular concentrations of K+. The rise in [Ca2+]i stimulated by TG occurs in the absence of detectable production of inositol phosphates. Moreover, TG does not alter the early biochemical events of T cell activation triggered through the CD2 or the CD3 T cell antigens. Indeed, both inositol phosphate production and intracellular pH increase induced by specific monoclonal antibodies (mAb) remain unchanged after TG treatment. These data suggest that in human T lymphocytes TG releases Ca2+ from an intracellular pool by a mechanism which is independent of the phospholipase C metabolic pathway. Preincubation with TG of T cell clone P28 empties both the CD2 and the CD3-sensitive intracellular Ca2+ pool(s). Conversely, prestimulation of T cell clone P28 by CD3 or CD2-specific mAb inhibits the Ca2(+)-mobilizing effect of TG. Thus it appears that TG and CD2- or CD3-specific mAb mobilize Ca2+ from common Ca2+ pool(s). Taken together, these results demonstrate that Ca2+ influx in human T cells may be linked to mobilization of intracellular Ca2+ pools and by a mechanism independent of phosphoinositide hydrolysis. They further indicate that the release of intracellular Ca2+ pool(s) may play a major role in the opening of cell membrane Ca2+ channels observed during the CD2- or CD3-induced stimulation of human T lymphocytes.

Antibodies, Monoclonal↗
PubMed2000

Intracellular delivery of phosphoinositides and inositol phosphates using polyamine carriers.

Phosphoinositide signaling regulates events in endocytosis and exocytosis, vesicular trafficking of proteins, transduction of extracellular signals, remodeling of the actin cytoskeleton, regulation of calcium flux, and apoptosis. Obtaining mechanistic insights in living cells is impeded by the membrane impermeability of these anionic lipids. We describe a carrier system for intracellular delivery of phosphoinositide polyphosphates (PIP(n)s) and fluorescently labeled PIP(n)s into living cells, such that intracellular localization can be directly observed. Preincubation of PIP(n)s or inositol phosphates with carrier polyamines produced complexes that entered mammalian, plant, yeast, bacterial, and protozoal cells in seconds to minutes via a nonendocytic mechanism. Time-dependent transit of both PIP(n)s and the carrier to specific cytosolic and nuclear compartments was readily visualized by fluorescence microscopy. Platelet-derived growth factor treatment of NIH 3T3 fibroblasts containing carrier-delivered phosphatidylinositol 4,5-bisphosphate [PtdIns(4, 5)P(2)]-7-nitrobenz-2-oxa-1,3-diazole resulted in the redistribution of the fluorescent signal, suggesting that fluorescent PtdIns(4, 5)P(2) was a substrate for phospholipase C. We also observed a calcium flux in NIH 3T3 cells when complexes of carrier and PtdIns(4, 5)P(2) or inositol 1,4,5-trisphosphate were added extracellularly. This simple intracellular delivery system allows for the efficient translocation of biologically active PIP(n)s, inositol phosphates, and their fluorescent derivatives into living cells in a physiologically relevant context.

3T3 Cells↗
PubMed1977

Isolation and separation of inositol 1-phosphate, cyclic inositol 1,2-phosphate, and glycerylphosphoinositol from tissue culture cells labeled with [3H]inositol.

Water-soluble phosphorylated inositol derivatives have been separated from each other and from inositol by ion exchange and by thin-layer chromatography. The method, in combination with radioactive labeling, is sensitive enough to be applied to single tissue culture dishes corresponding to 10(6) - 10(7) cells. With this technique glycerylphosphoinositol, inositol 1-phosphate, cyclic inositol 1,2-phosphate, and at least three other inositol labeled compounds can be detected in human, monkey, hamster, mouse, and Japanese quail fibroblasts. During a 24-h incubation with [3H]inositol the extent of labeling of these compounds differed according to the cell type.

Animals↗
PubMed1994

Effect of chronic haloperidol treatment on dopamine-induced inositol phosphate formation in rat brain slices.

The effects of chronic haloperidol administration on the accumulation of inositol phosphates were examined in rat brain slices pre-labeled with [3H]myo-inositol and incubated with various dopaminergic drugs. Rats were treated with haloperidol-decanoate or its vehicle (sesame oil) for two, four or six weeks. Dopamine and the selective D1 agonist, SKF38393, induced a significant increase in lithium-dependent accumulation of [3H]inositol monophosphate (IP1) in the frontal cortex, hippocampus and striatum of vehicle-treated animals, while the selective D2 agonist quinpirole did not show any effect on IP1 accumulation. The actions of dopamine and SKF38393 were blocked by the D1 antagonist, SCH23390, but not by the D2 antagonist, spiperone, in all three brain regions. Haloperidol treatment did not affect basal phosphoinositide turnover in the three brain regions. Four or six weeks of haloperidol treatment significantly decreased dopamine-induced IP1 accumulation in the striatum (by 30% and 25%, respectively), but not in the frontal cortex and the hippocampus. Four weeks of treatment with haloperidol significantly decreased IP1 levels in the striatal slices when measured in the presence of quinpirole. However, the accumulation of IP1 measured in the presence of SKF38393 was not significantly altered after haloperidol treatment. The loss of dopamine-sensitive IP accumulation was not observed in the presence of spiperone after haloperidol treatment. The number, but not the affinity, of [3H]sulpiride binding sites in the striatum was significantly increased (by 34-46%) after chronic haloperidol treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Potentiation of [3H]inositol phosphate formation by receptor activation and membrane depolarization in brain cortical slices (I).

Potentiation of [3H]inositol phosphate ([3H]IP) accumulation by receptor agonists combined with depolarizing agents was studied in rat brain cortical slices, prelabeled with [3H]inositol. Muscarinic agonists, alpha 1-adrenergic, histaminergic and serotonergic agonists remarkably enhanced (2-7-fold) the accumulation of [3H]IP in the presence of KCl (30 mM). The potentiated levels of [3H]IP were strongly dependent on K+ concentration and displayed a dose-response relationship with the agonist. Other depolarizing agents such as veratridine and ouabain induce potentiation of [3H]IP formation similarly to that observed by KCl, but to a lesser extent. The production of elevated levels of [3H]IP is Ca2+-dependent with maximal effect at 0.6 mM which is similar to the Ca2+ dependency observed for the agonist and the depolarizing agent alone. Enhanced [3H]IP levels induced by agonists in the presence of depolarizing agents affect Vmax values only, since the apparent half maximal effective concentration of carbachol (CCh)-induced-IP-formation (1.2 x 10(-4) M) and of the phenylephrine-induced IP-formation (8 x 10(-6) M), were not affected in the presence of either K+ or veratridine. In addition the efficacy of various muscarinic agonists as inducers of IP-accumulation was conserved under depolarizing conditions as compared to IP accumulation under normal conditions. In the presence of KCl (30 mM) the maximal degree of potentiation was at a range of 5-7-fold, with order efficacy of ACh greater than CCh greater than Oxo M greater than arecoline much greater than pilocarpine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed2001

Regulator of G-protein signaling 3 (RGS3) inhibits Gbeta1gamma 2-induced inositol phosphate production, mitogen-activated protein kinase activation, and Akt activation.

Regulator of G-protein signaling 3 (RGS3) enhances the intrinsic rate at which Galpha(i) and Galpha(q) hydrolyze GTP to GDP, thereby limiting the duration in which GTP-Galpha(i) and GTP-Galpha(q) can activate effectors. Since GDP-Galpha subunits rapidly combine with free Gbetagamma subunits to reform inactive heterotrimeric G-proteins, RGS3 and other RGS proteins may also reduce the amount of Gbetagamma subunits available for effector interactions. Although RGS6, RGS7, and RGS11 bind Gbeta(5) in the absence of a Ggamma subunit, RGS proteins are not known to directly influence Gbetagamma signaling. Here we show that RGS3 binds Gbeta(1)gamma(2) subunits and limits their ability to trigger the production of inositol phosphates and the activation of Akt and mitogen-activated protein kinase. Co-expression of RGS3 with Gbeta(1)gamma(2) inhibits Gbeta(1)gamma(2)-induced inositol phosphate production and Akt activation in COS-7 cells and mitogen-activated protein kinase activation in HEK 293 cells. The inhibition of Gbeta(1)gamma(2) signaling does not require an intact RGS domain but depends upon two regions in RGS3 located between acids 313 and 390 and between 391 and 458. Several other RGS proteins do not affect Gbeta(1)gamma(2) signaling in these assays. Consistent with the in vivo results, RGS3 inhibits Gbetagamma-mediated activation of phospholipase Cbeta in vitro. Thus, RGS3 may limit Gbetagamma signaling not only by virtue of its GTPase-activating protein activity for Galpha subunits, but also by directly interfering with the activation of effectors.

Animals↗
PubMed1990

Production of inositol phosphates in BALB/C 3T3 cells stimulated with basic fibroblast growth factor.

When quiescent 3T3 fibroblast cells were pre-labelled with [3H]inositol and stimulated with basic fibroblast growth factor there was a stimulation of the hydrolysis of membrane lipids and the rapid production of [3H]inositol polyphosphates. Rapid and transient peaks of isomers of inositol phosphates with the chromatographic properties of inositol trisphosphates and inositol tetrakisphosphates were detectable by anion-exchange HPLC between 5 and 10 s after stimulation. These data suggest that upon stimulation the receptor for fibroblast growth factor is coupled to a phosphoinositidase C and that one of its signal-transducing pathways involves hydrolysis of inositol lipids and the production of inositol polyphosphates, some of which may act as intracellular signals mediating the cellular response. Chronic stimulation with basic fibroblast growth factor is associated with desensitization of the inositol lipid signaling pathway.

Animals↗
PubMed2001

Effect of several germination conditions on total P, phytate P, phytase, and acid phosphatase activities and inositol phosphate esters in rye and barley.

Two assays were conducted to study the evolution of rye and barley phosphatases (phytase and acid phosphatase) and the degradation of its substrates (inositol phosphate esters) during seed germination. In this manner we could obtain a low-phytate, endogenous phosphatase rich ingredient to be used in animal nutrition. In the first assay, the seeds were soaked for 1 and 14 h and germinated for 3 and 5 days with and without the addition of gibberellic acid (GA3). In the second assay, the seeds were soaked for 1 h and germinated for 1, 3, and 5 days with GA3. Phytase (up to 5739 and 3151 U x kg(-1)) and acid phosphatase (up to 18288 and 3151 U x g(-1)) activities, and IP6 (6.09 and 6.01 mg x g(-1)), IP5 (0.48 and 0.48 mg x g(-1)), and IP4 (0.13 and 0.06 mg x g(-1)) were detected in ungerminated rye and barley, respectively. The germination process caused a significant increase of Phy and AcPh activities in rye (up to 112 and 213%) and barley (up to 212 and 634%) and a reduction in the phytate phosphorus content (up to 84 and 58%, respectively). Phytate phosphorus content was affected only by soaking time in the case of rye. Finally, during the course of germination, IP6 and IP5 were rapidly degraded in rye (88 and 79%) and barley (67 and 52%), and IP4 was only a short-living intermediate, which was increased during hydrolysis and degraded to IP3. In conclusion, a marked increase of Phy and AcPh activities in rye and barley with a concomitant decrease in phytate phosphorus content and an increase in the content of lower inositol phosphates were observed during the rye and barley germination.

6-Phytase↗
PubMed1996

Inhibition by toxin B of inositol phosphate formation induced by G protein-coupled and tyrosine kinase receptors in N1E-115 neuroblastoma cells: involvement of Rho proteins.

G protein-coupled receptors activate phospholipase C (PLC)-beta isoforms by the alpha or beta gamma subunits of G proteins, whereas growth-factor receptors activate PLC-gamma isoforms by phosphorylating tyrosine residues of the enzyme. As a common substrate for PLC enzymes, phosphatidylinositol 4,5-bisphosphate [Ptdins(4,5)P2] may play a pivotal role in the regulation of cellular PLC activity. Because small-molecular-weight G proteins have been implicated in the synthesis of Ptdins(4,5)P2, we studied the effect of Clostridium difficile toxin B, which glucosylates and thereby inactivates small G proteins of the Rho family, on receptor-stimulated PLC activity. We report here that in N1E-115 neuroblastoma cells, stimulation of inositol phosphate formation by the G protein-coupled receptor agonists bradykinin and lysophosphatidic acid and by the tyrosine kinase receptor agonist platelet-derived growth factor is largely attenuated by toxin B treatment. Furthermore, inositol phosphate production stimulated by the stable GTP analog guanosine 5'-O-(3-thio)-triphosphate in permeabilized N1E-115 cells was inhibited by C3 exoenzyme, which specifically inactivates Rho proteins. The inhibition by toxin B was apparently not caused by its effect on the cytoskeleton. In addition, the level of platelet-derived growth factor receptors, which was studied with immunoblotting, was unaffected by toxin B. Using exogenous Ptdlns(4,5)P2 as PLC substrate, it was found that the intrinsic enzymatic activity of PLC activated either by Ca2+ or by guanosine 5'-O-(3-thio)triphosphate was not altered by toxin B. However, toxin B decreased strongly, by up to 80%, the cellular level of Ptdins(4,5)P2 in a concentration-dependent manner, without changing those of phosphatidylinositol and phosphatidylinositol 4-phosphate. These results, together with the recent finding that Rho family proteins can regulate phosphatidylinositol 4-phosphate 5-kinase activity, demonstrate that Rho proteins are presumably important regulators of Ptdins(4,5)P2 synthesis and, thereby, play an integral role in the regulation of cellular signaling by PLC enzymes.

ADP Ribose Transferases↗
PubMed1993

Methyl mercury increases intracellular Ca2+ and inositol phosphate levels in cultured cerebellar granule neurons.

In an effort to explain the previously observed methyl mercury (MeHg)-induced stimulation of protein phosphorylation in cerebellar granule neuron cultures, the effect of MeHg on protein kinase activities in cell-free assays and on second messenger systems in cultured neurons has been examined. Using cell-free assays for several protein kinases, no stimulation of enzyme activity was found at any concentration of MeHg tested. After 24 h exposure, 1-5 microM MeHg was found to have no significant effect on neuronal cyclic AMP levels. In contrast, intracellular levels of Ca2+ and rates of 45Ca2+ uptake were elevated 2.2-fold and 3.6-fold, respectively, by 5 microM MeHg. These effects were not observed with mercuric chloride, triethyllead, or lead acetate. Measurement of inositol phosphate production in granule cell cultures revealed a sensitive, pretoxic effect of MeHg with twofold stimulation following 30-min exposure to 5 microM MeHg and 1.6-fold after 24-h exposure to 3 microM MeHg. Detection of inositol phosphate production after 30 min of MeHg was largely neuron-specific. These results suggest that second messenger-mediated activation of select protein kinase enzymes may be the mechanism underlying MeHg-induced stimulation of protein phosphorylation in cerebellar neuronal culture. In addition, these findings indicate a specific interference with neuronal signal transduction and suggest a basis for the selective neurotoxic action of this agent.

Animals↗
PubMed1995

Inositol phosphates have novel anticancer function.

Inositol hexaphosphate (InsP6, phytic acid) is ubiquitous in the plant kingdom and is abundant in cereals and legumes. In much smaller amounts InsP6 and its lower phosphorylated forms (InsP1-5) are contained in most mammalian cells, where they are important in regulating vital cellular functions. Both in vivo and in vitro experiments have suggested striking anticancer potential (preventive as well as therapeutic) for InsP6 with and without inositol. In addition to reduce cell proliferation, InsP6 increases differentiation of malignant cells often resulting in reversion to the normal phenotype. InsP6 is quickly absorbed from the rat stomach and upper intestine and distributed as inositol and InsP1. In vitro it is instantaneously taken up by malignant cells undergoing variable dephosphorylation to inositol and InsP1-5, pointing toward their role in mediating the action of InsP6. Because InsP6 is high in high-fiber diets, our studies also may explain, at least in part, the epidemiologic observation showing high-fiber diets are associated with a lower incidence of certain cancers. Although further studies are needed to elucidate the mechanism(s) of this action, inclusion of InsP6 in our strategies for cancer prevention and therapy is warranted.

Animals↗
PubMed1993

Reconstitution of a T cell receptor-stimulated plasma membrane calcium transporter: lack of dependence on inositol phosphates.

The activation of T lymphocytes, like many cells, requires a rapid rise in intracellular Ca2+ secondary to both an influx and a release from intracellular stores. The latter is activated by inositol-1,4,5-trisphosphate [Ins(1,4,5)P3]. It is controversial if inositol phosphates can also stimulate a plasma membrane Ca2+ channel in T cells. We have studied the human T cell line HPB-ALL which, upon stimulation of its antigen receptor, does not generate detectable levels of Ins(1,4,5)P3 or internal Ca2+ release, but does have a Ca2+ influx. We have reconstituted a receptor-activated Ca2+ transporter from plasma membranes from these cells which has properties similar to the transporter observed in vivo and does not require inositol phosphates for activation. These data show that mitogens may activate more than one type of ligand-gated Ca2+ transport mechanism in T lymphocytes.

Antibodies, Monoclonal↗
PubMed1997

Cortical [3H]ketanserin binding and 5-HT2A receptor-mediated inositol phosphate production in the spontaneously hypertensive rat and Lewis rat strains.

The spontaneously hypertensive rat (SHR) and Lewis rat strains differ in the elevated plus-maze of anxiety, the former and the latter strain displaying low and high anxiety, respectively. A recent study has shown that serotonin (5-hydroxytryptamine, 5-HT)2A receptor-mediated head shakes, but not [3H]ketanserin binding at these receptors, are less in Lewis rats, compared with SHRs. Herein, we have analysed the hypothesis of a difference in 5-HT2A receptor-effector coupling between these two strains. Confirming our previous results, the Bmax and KD values for the specific [3H]ketanserin binding at cortical 5-HT2A receptors were respectively identical in both strains. The accumulation of total inositol phosphates by the 5-HT2A,2B,2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 0.01-100 microM) was concentration- and strain (Lewis > SHR)-dependent. Preincubation with 0.01 and 0.1 microM of the 5-HT2A receptor antagonist SR 46349B, respectively, decreased and prevented DOI-elicited inositol phosphate production in both strains. The aforementioned genetic differences in 5-HT2A receptor-mediated head shakes may thus lie at some point distal from the 5-HT2A receptor.

Amphetamines↗
PubMed2001

Expression of functional luteinizing hormone (LH) receptor and its messenger ribonucleic acid in bovine endometrium: LH augmentation of cAMP and inositol phosphate in vitro and human chorionic gonadotropin (hCG) augmentation of peripheral prostaglandin in vivo.

Bovine endometrium contains LH/hCG binding sites and LH increases endometrial production of prostaglandin H synthase-2 (PGHS-2) and prostaglandin synthesis. This study showed that uterine endometrium contained both LH receptor mRNA transcript and a 93-kDa immunoreactive protein that bound to anti-rat LH receptor antibody. LH receptor and its mRNA were expressed maximally in the endometrium of cows from the luteal phase compared to the follicular phase of the estrous cycle. Furthermore, there was a response shown when incubation of endometrial minces from both pre-estrus/estrus and luteal phase (but not post-ovulatory phase) with LH or oxytocin (20 ng/ml) that resulted in a significant (p<0.02) increase in cAMP and total inositol phosphates. When Day 15 cows were injected i.v. with 3000 units hCG, the increase in peripheral 13,14-dihydro-15-keto PGF(2alpha) was 2.5-fold higher than saline controls or oxytocin. We conclude that LH stimulates endometrial cAMP and total inositol phosphates which results in increased formation of uterine PGHS-2 similar to LH effect on ovarian PGHS-2. The increased 13,14-dihydro-15-keto PGF(2alpha) production induced in vivo by injections of hCG indicates that LH may have a reinforcing role in luteolysis.

Animals↗