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PubMed1991

Age-related changes in receptor-mediated phosphoinositide hydrolysis in various regions of rat brain.

The effects of age on cholinergic markers and receptor-stimulated phosphoinositide hydrolysis was examined in the frontal cortex and striatum of male Fischer-344 rats. Choline acetyltransferase activity was decreased 27% in the striatum of aged (24 month) rats compared to young (3 month) controls. Muscarinic receptor density as measured by [3H]-quinuclidinyl benzilate binding showed a similar 26% decrease in the striatum of aged rats. Phosphoinositide hydrolysis was measured by the release of inositol phosphate (IP) from tissue slices prelabeled with [3H]myoinositol in response to carbachol, norepinephrine, and quisqualate. In the cortex, stimulated IP release was significantly greater in slices from aged rats compared to young rats for all three agonists. In contrast, stimulated IP release was significantly decreased in striatal slices from aged rats compared to young for all three agonists. These data indicate a differential effect of age on agonist-stimulated phosphoinositide hydrolysis in the cortex and striatum. The decreased responsiveness in the latter area may result from the age-related loss of postsynaptic receptors.

Aging↗

PubMed1987

Depolarisation-evoked release of acetylcholine can mediate phosphoinositide hydrolysis in slices of rat cerebral cortex.

Depolarisation of [3H]inositol prelabelled slices of cerebral cortex of the rat, with elevated extracellular K+ or the alkaloid veratrine, induced a marked accumulation of [3H]inositol monophosphate in the presence of 5 mM Li+. The effects of these stimuli were concentration-related with maximal responses obtained at 30 mM K+ and 30 microM veratrine. Larger concentrations produced submaximal responses but also markedly suppressed the incorporation of [3H]inositol into phospholipid. The responses to K+ or veratrine were not sensitive to atropine, prazosin, mepyramine, ketanserin or the peptidase inhibitor bacitracin. However, in the presence of the cholinesterase inhibitor physostigmine, the responses to these stimuli were greatly enhanced and this could be blocked by atropine. Both veratrine and K+ markedly stimulate release of endogenous acetylcholine from the slices. Release appears to be linear with time over the 45 min period of continuous stimulation. Reduction of extracellular calcium severely suppressed both the release of acetylcholine and the atropine-sensitive component of the phosphoinositide response to K+. The results suggest that endogenous acetylcholine can stimulate phosphoinositide metabolism by interacting with muscarinic receptors. The atropine-insensitive component, at least in part, represents entry of Ca2+ through voltage-sensitive channels and perhaps a direct effect on phosphoinositide metabolism.

Acetylcholine↗

PubMed1993

Synergistic activation of phosphoinositide hydrolysis induced in brain slices by norepinephrine and the excitatory amino acid agonist, trans-ACPD.

Norepinephrine and trans-1-aminocyclopentyl-1,3-dicarboxylic acid (ACPD) each individually stimulated hydrolysis of phosphoinositides and when tested in combination caused a stimulation that was 50-90% greater than additive in hippocampal and cortical slices of the rat but not in striatal slices. This synergistic augmentation of hydrolysis of phosphoinositide was evident with all stimulatory concentrations of norepinephrine and of ACPD up to 1 mM, at which point ACPD was inhibitory. A time-course study revealed no lag in the synergistic interaction and no down-regulation through 60 min of incubation of the augmented response to the combined agonists. The synergistic reaction was mediated by alpha 1-adrenergic receptors and by metabotropic excitatory amino acid receptors. Increased intracellular calcium, but not activation of protein kinase C, may play a role in mediating the synergistic interaction. Thus, a unique synergistic stimulatory interaction was found between two receptors coupled with phosphoinositide metabolism, a finding which also supports the suggestion that these two systems are co-localized in some cells.

Animals↗

PubMed1991

Effect of maitotoxin analogues on calcium influx and phosphoinositide breakdown in cultured cells.

Maitotoxin (MTX) and the analogues, bis-desulfated-MTX (didesulfo-MTX), mono-desulfated-MTX (monodesulfo-MTX), and hydrogenated-MTX (H-MTX) were examined on 45Ca2+ influx and phosphoinositide breakdown with hamster insulinoma HIT cells and rat glioma C6 cells. The activity of MTX was greatly reduced either by desulfation or by hydrogenation. Didesulfo-MTX weakly stimulated calcium influx in HIT cells, but had no stimulatory effect on either calcium influx or phosphoinositide breakdown in C6 cells. All the analogues inhibited MTX-induced calcium influx in either HIT or C6 cells. Didesulfo-MTX inhibited the calcium influx elicited by 3 ng/ml MTX in C6 cells with an IC50 of 7.0 +/- 0.7 ng/ml. The data suggest that the sulfate groups in MTX are important for stimulation of calcium influx and phosphoinositide breakdown, but are not essential for binding to a receptor-site on cell membranes. Although catalytic reduction of double bonds in MTX reduced activity by nearly 100-fold, a tritiated H-MTX still represents a potential radioligand for identification of MTX-binding sites.

Animals↗

PubMed1991

Muscarinic acetylcholine receptor-mediated phosphoinositide turnover in cultured human retinal pigment epithelium cells.

Cultured retinal pigment epithelium cells prepared from post-mortem adult human eyes are shown to contain muscarinic receptors associated with phosphoinositide turnover. Carbachol at a concentration of 100 microM induced a four-fold increase in 3H-inositol phosphates (more than 76% is in the form of 3H-inositol-1-phosphate) accumulation within 45 min in cells prelabelled with 3H-myoinositol and exposed to 5 mM LiCl. The EC50 of carbachol was approx. 70 microM and the saturation concentration was about 1 mM. The carbachol-induced response was blocked by both atropine and pirenzepine, the former being most effective. Pre-exposure of cells to carbachol resulted in desensitization and a drastic reduction in the subsequent carbachol-induced stimulation of 3H-inositol phosphates. The carbachol response could be attenuated by the biologically active phorbol ester, 4 beta-phorbol 12-myristate 13-acetate, and this was nullified by the protein kinase C inhibitor, staurosporine. The biologically inactive phorbol ester, 4 alpha-phorbol 12,13 dideconoate, did not attenuate the carbachol-induced stimulation of 3H-inositol phosphates. Pertussis toxin failed to influence the carbachol receptor-mediated phosphoinositide turnover. These studies provide clear evidence for the occurrence of muscarinic receptors coupled to phosphoinositide hydrolysis on human retinal pigment epithelium cells.

Adult↗

PubMed1996

Effects of excitatory amino acids on phosphoinositide metabolism in frog retina.

The effects of excitatory amino acid receptor agonists on the hydrolysis of phosphoinositides were examined using frog retinal membranes prelabeled in vitro with either 32PO4 or [3H]inositol. Glutamate stimulated release of [3H]inositol phosphates (IPs) from the retinas and altered the 32P-labeling pattern of phosphatidylinositol (PI) cycle intermediates. This indicates that glutamate affects not only the hydrolysis of phosphoinositides but possibly other steps involved in the PI cycle. Among glutamate analogs, kainate (KA), quisqualate (QA), and, to a lesser extent, N-methyl-D-aspartate (NMDA) mimicked the glutamate effect, whereas L-2-amino-4-phosphonobutyrate (L-AP4) was not effective in causing either the accumulation of [3H]IPs or the alteration of the 32P-labeling pattern of PI cycle intermediates. Among QA specific agonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), but not ibotenate (IBO) or trans-1-aminocyclopentane-1,3-dicarboxylate (ACPD) was active in stimulating IPs formation. KA effect on IPs formation may be due to indirect (polysynaptic) activation of receptor(s) other than L-AP4, IBO, or ACPD specific QA receptors. To avoid activating polysynaptic pathways, retinal synaptoneurosomes prelabeled with [3H]inositol were used to examine the hydrolysis of phosphoinositides. As in whole retinas, KA, carbachol (CARB), and NMDA stimulated the release of IPs while L-AP4 had minimal effect. Glycine (GLY) had no effect. Our results show CARB and KA to be the most effective in stimulating the production of IPs. Their effects were exerted directly through separate receptors and not through polysynaptic pathways. ACPD and IBO were the least effective in eliciting the release of IPs. Our studies provide evidence that ionotropic and not metabotropic glutamate receptors are involved in PI metabolism in the retina.

Animals↗

PubMed1988

Phosphorylation of the outer surface of platelets enhances the effects of collagen on aggregation, ATP release, calcium translocation and phosphoinositide hydrolysis.

Phosphorylation of the outer surface of human platelets increases their functional responsiveness to subthreshold amounts of collagen. Collagen-stimulated platelet aggregation, release of ATP and changes in cytoplasmic ionized calcium levels were all enhanced by pretreatment with ATP plus a kinase purified from human plasma. [3H]-myo-inositol-labeled human platelets were used to investigate the possible role of phosphoinositide metabolism in mediating this enhanced responsiveness. Formation of inositol mono-, bis-, and trisphosphate in response to collagen was more pronounced in phosphorylated platelets than in control platelets. Collagen-stimulated inositol phosphate production in both control and phosphorylated platelets was completely inhibited by the addition of 20 microM indomethacin. Of a range of agents that stimulated phosphoinositide hydrolysis, only the response to collagen was enhanced by phosphorylation. The plasma protein kinase was shown to catalyse phosphorylation of the collagen receptor. These data indicate that the enhanced phosphoinositide hydrolysis resulting from phosphorylation of the collagen receptor might be linked to the increased functional responses to collagen.

Adenosine Triphosphate↗

PubMed1989

Human alpha-thrombin induces phosphoinositide turnover and Ca2+ movements in cultured human umbilical vein endothelial cells.

This report shows that purified human alpha-thrombin was able to stimulate a rapid and transient formation of water-soluble phosphorylated 3H-inositols in cultured human umbilical vein endothelial cells (HUVEC) prelabelled with 3H-inositol. A parallel breakdown and resynthesis of 3H-inositol-containing phospholipids was observed. Simultaneously, thrombin induced a transient increase of intracellular free Ca2+[( Ca2+]i), as measured from increased fluorescence of quin2 loaded cells. Phosphoinositide turnover and Ca2+ mobilization showed a similar dependence on thrombin dose. [Ca2+]i rise resulted from both influx from extracellular medium and redistribution from intracellular storage sites. On the other hand thrombin-induced phosphoinositide hydrolysis was not dependent on [Ca2+]i rise. [Ca2+]i elevation might be, at least partially, a consequence of increased phosphoinositide turnover, as suggested by [Ca2+]-mobilizing activity of inositol-trisphosphate in other cells.

Anti-Bacterial Agents↗

PubMed1989

Receptors that inhibit phosphoinositide breakdown.

Calcium-mobilizing receptors are believed to activate phospholipase C. Joel Linden and Thérèse Mary Delahunty summarize recent reports which indicate that activation of some receptors that inhibit the accumulation of Ca2+ within cells - notably receptors for adenosine, dopamine and several other neurotransmitters - can inhibit phosphoinositide metabolism. Two types of mechanism may be involved in these responses. Many instances of receptor-mediated inhibition of phosphoinositide breakdown can be detected only after a period of several minutes and may be secondary to receptor-mediated events that lower [Ca2+]i or activate certain protein kinases. In other instances the activation of receptors rapidly (within seconds) inhibits phosphoinositide breakdown, possibly via the activation of guanine nucleotide binding proteins that either directly, or by a rapid indirect action, inhibit phospholipase C. Putative mechanisms for direct and indirect regulation of phospholipase C are discussed.

Animals↗

PubMed1993

Novel Ca2+ channels underlying transduction in Drosophila photoreceptors: implications for phosphoinositide-mediated Ca2+ mobilization.

Drosophila photoreceptors are excellent models for studies of the ubiquitous phosphoinositide signalling cascade. Recent studies suggest that light-induced phosphoinositide hydrolysis in Drosophila leads to the activation of two classes of channels. One is selective for Ca2+ and absent in the transient receptor potential mutant trp. The trp gene product, which shows some structural similarity to vertebrate voltage-gated Ca2+ channels, may thus define a novel family of second-messenger-operated Ca2+ channels generally responsible for the widespread but poorly understood phenomenon of phosphoinositide-mediated Ca2+ entry. The other channel is a non-selective cation channel that requires Ca2+ for activation. As well as being a major charge carrier for the light-induced current, Ca2+ influx via the trp-dependent channels appears to be required for refilling Ca2+ stores sensitive to inositol 1,4,5-trisphosphate and for feedback regulation (light adaptation) of the transduction cascade.

Animals↗

PubMed1986

Cyclic AMP inhibition of phosphoinositide turnover in human neutrophils.

The effect of increased intracellular levels of cyclic AMP on phosphoinositide metabolism was studied in human neutrophils stimulated with fMet-Leu-Phe. Intracellular cyclic AMP was raised by preincubation either with dibutyryl cyclic AMP and theophylline or with prostaglandin E1. Concentrations of dibutyryl cyclic AMP and theophylline fully inhibitory for the metabolic responses inhibited phosphoinositide breakdown and phosphatidic acid formation to a large extent. The accumulation of the water-soluble inositol phosphates was also measured. In agreement with the data obtained on the phospholipids, inositol phosphate generation was found to be severely, though not completely, reduced. Treatment with dibutyryl cyclic AMP and theophylline also inhibited resynthesis of membrane inositol lipids. Treatment with prostaglandin E1 had a similar, though less, marked effect on inositol lipid turnover, which was parallel with a smaller inhibition of metabolic responses. We therefore suggest that the elevation of intracellular cyclic AMP mainly affects neutrophil responses by inhibiting the phosphoinositide cycle.

Alprostadil↗

PubMed1989

Stimulatory effects of atrial natriuretic factor on phosphoinositide hydrolysis in cultured bovine aortic smooth muscle cells.

The effects of atrial natriuretic factor (ANF) on phosphoinositide hydrolysis were examined in preparations of cultured bovine aortic smooth muscle cells. In homogenates or particulate fractions from cultured bovine aortic smooth muscle cells, ANF and atriopeptin I increased the formation of inositol phosphates and GTPase activity. The effects on inositol phosphates were markedly enhanced with guanosine 5'[gamma-thio]triphosphate. Both atrial peptides also stimulated the formation of diacylglycerol in intact cultured cells. In these experiments, atriopeptin I was about 10-fold more potent than ANF. These studies indicate that atrial peptides have stimulatory effects on phosphoinositide hydrolysis which are mediated through a guanine nucleotide regulatory protein. The greater potency of atriopeptin I on GTPase activity and the accumulation of inositol phosphates suggests that the nonguanylate cyclase-coupled receptor for ANF (ANF-R2) mediates the stimulatory effects of ANF on phosphoinositide hydrolysis through a guanine nucleotide regulatory protein.

Animals↗

PubMed1991

Altered phosphoinositide-specific phospholipase C and adenylyl cyclase in brain cortical membranes of cats with GM1 and GM2 gangliosidosis.

Phosphoinositide-specific phospholipase C and adenylyl cyclase were studied in brain cortical membranes from cats with GM1 and GM2 gangliosidosis. In contrast to brain cortical membranes from unaffected control cats, phospholipase C acting against exogenously supplied phosphoinositide substrates did not respond to stimulation by GTP gamma S, carbachol or fluoroaluminate in cortical membranes of cats with gangliosidosis. However, the enzyme was activated by calcium in membranes from affected cats to the same extent as in membranes from control cats. Basal adenylyl cyclase activity was increased 3-fold in cortical membranes of cats with GM1 and GM2 gangliosidosis, compared with unaffected sibling controls. Fluoroaluminate was equally effective in stimulating adenylyl cyclase in controls and in membranes of affected and normal cats. In addition, GppNHp was able to inhibit the forskolin-activated enzyme both in membranes from cats with gangliosidosis and sibling controls. These data suggest that the activation of phosphoinositide-specific phospholipase C in brain membranes by guanine nucleotide binding proteins is markedly impaired in GM1 and GM2 gangliosidoses.

Adenylyl Cyclases↗

PubMedDate not supplied

Aging-induced decrease in dopaminergic-stimulated phosphoinositide metabolism in rat brain.

Accumulation of [3H]inositol phosphate and [3H]inositol labeling of phosphoinositides were evaluated in brain slices of 3-, 6-, 12-, and 24-month-old Fischer-344 rats. The dopamine agonist, SKF38393, stimulated significantly lower accumulations of inositol trisphosphate, inositol bisphosphate, and inositol monophosphate in the striatum, hippocampus, and frontal cortex of 24-month-old rats compared with the 6-month-old animals. No differences, however, were observed between the 3, 6, and 12-month-old groups. Furthermore there were marked decrements of 41% to 58% in the labeling of phosphoinositides in the different brain regions of the aged animals. Dose-response studies in forebrain slices of the 6-month-old and 24-month-old animals showed aging-related decrements of 53% (p less than 0.001) and 48% (p less than 0.001) in the maximal SKF38393-stimulated labeling of phosphoinositides and accumulation of inositol phosphates, respectively. These data suggest that aging of the rat brain is associated with alterations in the basal turnover of the inositol cycle and in the sensitivity of the transduction pathway to dopamine receptor stimulation.

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

PubMedDate not supplied

Impaired phosphoinositide hydrolysis in Alzheimer's disease brain.

The effect of Alzheimer's disease (AD) on the activity of the phosphoinositide second messenger system was studied by measuring the hydrolysis of [3H]phosphatidylinositol (PI) by membranes from postmortem human prefrontal cortex. The activity of phospholipase C was similar in AD and control tissue. Activation with GTP gamma S and with carbachol demonstrated less [3H]PI hydrolysis in AD than control membranes. The concentration of Gq/11, the G-proteins most likely functional in phosphoinositide metabolism, was unchanged in AD compared with controls, indicating that function of the receptor-G-protein complex rather than the G-protein concentration was the site of the impairment in AD. These results indicate that postsynaptic muscarinic receptor responses are impaired in AD, a finding that may explain, in part, the limited therapeutic responses achieved by administration of cholinomimetics to patients with AD. Also, this assay provides a means to identify cholinomimetics that are most effective in activating muscarinic receptor-coupled phosphoinositide hydrolysis in human brain, agents which should have the greatest potential for providing therapeutic responses in AD.

Aged↗

PubMed1986

Human growth hormone-stimulated mitogenesis of Nb2 node lymphoma cells is not mediated by an immediate acceleration of phosphoinositide metabolism.

Lactogenic hormones stimulate the mitogenesis of Nb2-11C rat lymphoma cells and this stimulation is enhanced by 12-O-tetradecanoyl phorbol ester (TPA). The effect of human growth hormone (hGH) and TPA on phosphoinositide metabolism in Nb2-11C cells was tested by measuring the incorporation of [3H]myo-inositol or 32P or measuring the breakdown of polyphosphoinositides in cells prelabeled with [3H]myo-inositol, 32P or [3H]arachidonic acid. We found that none of these processes is immediately stimulated by either hGH and/or TPA. Our results indicate that the overall phosphoinositide turnover is slow or confined to small fractions only. On the other hand, the phosphorylation-dephosphorylation cycle of polyphosphoinositides is quite fast and remarkably exceeds the rate of incorporation of [3H]myo-inositol. Our present results indicate, therefore, that the mitogenic effect of hGH and its enhancement by TPA is not mediated by an immediate increase in phosphoinositide metabolism.

Animals↗

PubMed1992

Paradoxical signal transduction mechanism of endothelins and sarafotoxins in cultured pituitary cells: stimulation of phosphoinositide turnover and inhibition of prolactin release.

Endothelins (ET-1, ET-2, ET-3 and vasoactive intestinal contractor, VIC) and sarafotoxins (SRTX-b and SRTX-c) appear to bind with high affinity to a homogeneous class of binding sites in cultured rat pituitary cells. All of these ligands seem to interact with the same receptor (ETA-R), except for SRTX-c which apparently binds to a separate receptor. Binding was followed by phosphodiesteric cleavage of phosphoinositides, resulting in the formation of inositol phosphates. No consistent effect on basal or gonadotropin-releasing hormone (GnRH)-induced release of luteinizing hormone (LH) was exerted by ET or SRTX during 2 h of static incubation. On the other hand, both groups of vasoactive peptides inhibited basal and thyrotropin-releasing hormone (TRH)-induced prolactin secretion. Surprisingly, activation of phosphoinositide turnover by TRH in pituitary mammotrophs led to stimulation of prolactin secretion, whereas activation of the same pathway by ET or SRTX resulted in inhibition of prolactin secretion. ET and SRTX stimulated inositol phosphate formation in GH3 cell line and in the gonadotroph-like cell line alpha T-3 (which is capable of producing the alpha subunit of the gonadotrophins), indicating that the peptides interact with both pituitary mammotrophs and gonadotrophs. The very low concentrations (nM range) needed to stimulate phosphoinositide turnover and to inhibit prolactin secretion, as well as the recent finding that ETs are present in the hypothalamo-pituitary axis suggest that ET might participate in the neuroendocrine modulation of pituitary functions. One such possibility is that ETs might be members of the prolactin inhibiting factors (PIFs) family.

Animals↗

PubMed1989

Phosphoinositides and GTP binding proteins involved in muscarinic generation of hippocampal rhythmic slow activity.

We examined the role of phosphoinositide turnover in muscarinic rhythmic slow activity (RSA; also called theta) in rat CA3 pyramidal neurons. Pre-incubation of hippocampal slices in pertussis toxin (which inhibits some GTP-binding proteins) or in Li+ (which blocks inositol phosphate degradation, and thereby decreases the resynthesis of phosphoinositides), prevented the induction of RSA by carbachol. Phorbol esters, which can activate protein kinase C (PKC) directly, did not induce RSA but inhibited muscarinic RSA. We infer that muscarinic RSA involves a GTP-binding protein linked increase in phosphoinositide turnover, while the activation of PKC may have a negative feedback role.

Action Potentials↗