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PubMed1989

Maitotoxin, a potent, general activator of phosphoinositide breakdown.

Maitotoxin (MTX), a potent marine toxin, elicits a calcium-dependent activation of cells that can be inhibited by calcium channel blockers like nifedipine. MTX also stimulates phosphoinositide breakdown in smooth muscle cells, NCB-20 cells and PC12 cells through a nifedipine-insensitive mechanism. We now report that MTX stimulates phosphoinositide breakdown in a wide variety of cells, and appears to represent the first general activator of this second messenger-generating system. MTX-induced stimulation of phosphoinositide breakdown is dependent in every cell line on the presence of extracellular calcium. In differentiated HL60 cells, in which a chemotactic peptide (fMLP) activates phosphoinositide breakdown via a pertussis toxin-sensitive mechanism, MTX-induced stimulation is not affected by pertussis toxin treatment. A phorbol ester has no effect on the response to MTX. Thus, MTX stimulates phosphoinositide breakdown through a calcium-dependent mechanism that at least in three cell lines (PC12, NCB20 and HL60) is not mediated by a pathway that involves a pertussis toxin-sensitive guanine nucleotide-binding protein.

Animals↗

PubMed1995

Interaction of ethanol and anoxia with muscarinic receptor--stimulated phosphoinositide metabolism during brain development.

The mechanism(s) by which ethanol induces alterations in brain development may involve direct actions (e.g. changes in specific biochemical pathways), or indirect effects, such as cerebral hypoxia resulting from ethanol - induced circulatory changes. Since both ethanol and hypoxia are known to affect the metabolism of phosphoinositides, which has been suggested as a possible target for ethanol's developmental neurotoxicity, in the present study we have investigated the in vitro effects of both severe hypoxia (anoxia) and ethanol (alone or in combination) on muscarinic receptor-stimulated phosphoinositide metabolism in cerebral cortex slices from neonatal rats. Anoxia markedly inhibited carbachol - stimulated phosphoinositide metabolism in adult rats (67%), but only slightly (10%) in neonatal animals. Reoxygenation reversed the effect of anoxia at both ages. On the other hand, ethanol's inhibitory effect was pronounced in neonatal rats only, and was additive to that of anoxia. The presence of ethanol did not affect the recovery of carbachol - stimulated phosphoinositide metabolism following anoxia and reoxygenation. These results indicate that ethanol and anoxia differently and independently affect muscarinic receptor - stimulated phosphoinositide metabolism and may mutually contribute to the CNS effects observed following developmental ethanol exposure.

Age Factors↗

PubMed1995

3,4-Diaminopyridine induced hydrolysis of phosphoinositide in cultured neurons from embryo chick forebrain.

The effect of 3,4-diaminopyridine (DAP) on phosphoinositide hydrolysis in cultured neurons from embryo chick forebrain has been studied. DAP produced a dose- and time-dependent accumulation of inositol phosphates. At 1 mM DAP a maximal effect was obtained. In Ca2+ free medium, DAP-activated turnover of phosphoinositide was reduced, but was still significant. Blocking Ca2+ entry with 200 microM Cd2+ also did not abolish the DAP-induced accumulation of inositol phosphates. As a comparison the effect of high K+ exposure was investigated. High K+ enhanced phosphoinositide hydrolysis, and this effect was also reduced by excluding Ca2+ influx. Moreover, DAP had no additional effect on the high K(+)-induced hydrolysis of phosphoinositide. Using oxonol-V, a depolarization of the membrane potential was seen in the neurons bathed in DAP containing medium. It is suggested that the depolarization may play a role in DAP-activated phosphoinositide turnover in cultured neurons of the embryo chick forebrain, but that Ca2+ entry is not necessary for this effect.

4-Aminopyridine↗

PubMed1995

Postnatal development of muscarinic receptor-stimulated phosphoinositide metabolism in mouse cerebral cortex: sensitivity to ethanol.

An enhanced coupling of cholinergic muscarinic receptors to phosphoinositide metabolism had been previously observed in brain from immature rat. This study reports that the postnatal development of muscarinic receptor-stimulated phosphoinositide metabolism is also enhanced in cerebral cortex slices from immature Swiss-Webster and Balb-c mice, as compared to adults. Response to the agonist carbachol was lower on postnatal day 3, peaked between days 5 and 12 and then declined to adult levels. Density of muscarinic binding sites, measured with the M1 ligand [3H]telenzepine on postnatal day 7, was, on the other hand, only half of the adult value. Phosphoinositide hydrolysis stimulated by glutamate decreased with age, while that elicited by norepinephrine increased. These results are also similar to those previously reported in the rat. Ethanol has been found to inhibit muscarinic receptor-stimulated phosphoinositide metabolism in rat brain in an age-dependent manner. This was confirmed in mouse brain, where ethanol inhibited this response in cerebral cortex of immature but not adult animals. These results indicate that the enhanced muscarinic receptor-stimulated phosphoinositide metabolism, which coincides with the brain growth spurt, is similar in rats and mice. Mice may be a useful species in which to genetically manipulate muscarinic receptors to gain a better understanding of their potential role in brain development.

Aging↗

PubMed1990

Local anesthetics: stimulation of incorporation of inositol into phosphoinositides in guinea pig cerebral cortical synaptoneurosomes.

Various local anesthetics enhanced the incorporation of [3H]inositol into phosphoinositides in guinea pig cerebral cortical synaptoneurosomes. Dibucaine, QX-572 and dimethisoquin showed maximum stimulation at 100 microM, tetracaine and diphenhydramine at 300 microM, and QX-314 at 1 mM, while quinacrine, lidocaine and cocaine showed no or only slight stimulation. There was no correlation between local anesthetic activity, estimated by inhibition of the 22Na+ flux elicited by the sodium channel activator batrachotoxin, and the potency for stimulation of inositol incorporation. A quaternary, relatively weak, local anesthetic, QX-572, was the most potent agent in stimulation of inositol incorporation, while the next most potent agent was dibucaine, a tertiary, very potent, local anesthetic. Dibucaine did not affect the uptake of [3H]inositol by synaptoneurosomes. The incorporation of [3H]inositol into phosphoinositides was increased in calcium-free buffer. The presence of dibucaine resulted in further stimulation of [3H]inositol incorporation in calcium-free buffer. Although dibucaine and QX-572 markedly stimulated incorporation of [3H]inositol into phosphoinositides, only QX-572 significantly enhanced the incorporation of 32PO4(3-) into phosphoinositides. The results suggest that certain local anesthetics enhance a pathway involving an exchange reaction between inositol and the phosphoinositol ester bond of phosphatidylinositol, but do not markedly affect the de novo pathway of phosphoinositide synthesis.

Anesthetics, Local↗

PubMed1995

Phosphatidylinositol 3-kinase: inhibition of intrinsic protein-serine kinase activity by phosphoinositides, and of lipid kinase activity by Mn2+.

Phosphatidylinositol (PI) 3-kinase is composed of 110 kDa catalytic and 85 kDa regulatory subunits. The 110 kDa subunit has two intrinsic kinase activities, i.e., Mn(2+)-dependent protein-serine kinase and Mg(2+)-dependent lipid kinase activities. These intrinsic kinases have been reported to be interdependent: protein-serine kinase phosphorylates the 85 kDa subunit of PI 3-kinase, which upon phosphorylation inhibits the lipid kinase activity of PI 3-kinase. We report here that phosphoinositides can selectively inhibit the protein-serine kinase activity of PI 3-kinase without affecting lipid kinase activity. This inhibition depends on the phosphorylation status of the phosphoinositides, i.e., PI 4,5-bisphosphate > PI 4-phosphate >> PI. Mn2+ (2 mM) protected protein kinase activity from phosphoinositides-mediated inhibition if added prior to interaction of PI 3-kinase with phosphoinositides. On the other hand, Mn2+ (2 mM) inhibited lipid kinase activity independent of its effect on the protein kinase activity of PI 3-kinase. The present study suggests that the protein-serine kinase and the lipid kinase activities of PI 3-kinase can be selectively inhibited by phosphoinositides and Mn2+ respectively.

Animals↗

PubMed1992

Regulation of bradykinin-induced phosphoinositide turnover in cultured cerebellar astrocytes: possible role of protein kinase C.

Phosphoinositide hydrolysis was studied in primary cultures of rat cerebellar astrocytes prelabeled with [3H]myo-inositol. Among the agonists examined, the rank order of efficacies in causing phosphoinositide hydrolysis was bradykinin > endothelin-1 > ATP > norepinephrine. The bradykinin response was robust (24-fold increase) with EC50 value of 30 nM and saturating concentration of 1 microM. Preincubation of cells with pertussis toxin did not affect the activation of phosphoinositide turnover by bradykinin. Although short-term (within 90 min) treatment of cells with phorbol dibutyrate attenuated bradykinin-induced phosphoinositide breakdown, the inhibitory effect was lost after 3-6 h of phorbol dibutyrate treatment. Extended (24 h) preincubation resulted in a potentiation of bradykinin response. Homologous desensitization of bradykinin response was observed in cells prestimulated with bradykinin for up to 6 h. However, similar to the effect of phorbol dibutyrate, 24-h pretreatment with bradykinin selectively sensitized the response to bradykinin. Up-regulation of the bradykinin response was also observed in cells prestimulated with endothelin-1 or norepinephrine for 24 h, although these treatments resulted in only homologous desensitization to their own response. Our results suggest that cultured cerebellar astrocytes express bradykinin receptors coupled to phospholipase C and in these cells protein kinase C plays a more prominent role in the negative-feedback regulation of bradykinin-evoked phosphoinositide response.

Adenosine Triphosphate↗

PubMedDate not supplied

Decreased phospholipase C-beta immunoreactivity, phosphoinositide metabolism, and protein kinase C activation in senescent F-344 rat brain.

Phosphoinositide metabolism, phospholipase C immunoreactivity, and protein kinase C translocation were measured in brain slices of 6- and 24-month-old F-344 rats. Basal phosphoinositide labeling and accumulation of [3H]inositol phosphates were reduced in the 24-month-old rats. The cholinergic agonist, carbachol, induced lower net accumulations of inositol phosphates in striatal, hippocampal, and cortical slices of the aged rats. The dose-response curve for carbachol showed a significantly lower maximal response in the striatum of senescent rats, whereas the time course of [3H]inositol incorporation into inositol metabolites and the accumulation of free [3H]inositol in tissues from young and old animals were not different. Quantitative analyses showed marked reductions in endogenous brain levels of the phosphoinositides and in phospholipase C-beta 1 immunoreactivity, but no marked reductions in endogenous brain levels of the phosphoinositides and in phospholipase C-beta 1 immunoreactivity, but no changes in phospholipase C-gamma levels in aged animals. Moreover, basal protein kinase C activity and carbachol-mediated translocation of the enzyme were significantly reduced in the cerebral cortex of the senescent animals. These findings imply that aging is associated with alterations in the brain content, metabolism, and activity of phosphoinositide-derived second messengers in the F-344 rat brain.

Aging↗

PubMed1981

Substrate requirements for the phosphoinositide response in rat pancreatic islets.

The relationship between phosphatidylinositol hydrolysis and the first phase of insulin secretion has been investigated by briefly exposing rat pancreatic islets that had been prelabelled with myo-[2-3H]inositol to various agonists and antagonists of insulin secretion. The recovery of lipid-bound radioactivity progressively decreased as the D-glucose concentration of the incubation medium was increased. Those carbohydrates that stimulated insulin secretion evoked a phosphoinositide response, whereas non-stimulatory carbohydrates did not. With the notable exception of amino acids, non-carbohydrate secretagogues were also found to decrease the islet lipid-bound radioactivity. Inhibition of islet glucose metabolism was found to decrease the recovery of lipid-bound radioactivity, largely as a result of impaired de novo phosphoinositide synthesis. The phosphoinositide response to glucose was not affected by inhibition of microtubular function, but was dependent upon the availability of extracellular calcium ions. We conclude that the phosphoinositide response in carbohydrate-stimulated islets is not directly related to the activation of membrane-associated glucose receptors, but may occur as a consequence of the subsequent transmembrane movement of calcium ions. Finally, the observation that stimulatory amino acids did not evoke a phosphoinositide response suggests that, under certain circumstances, this phenomenon can be dissociated from insulin secretion.

Animals↗

PubMed1995

Adenosine receptor activation potentiates phosphoinositide hydrolysis and arachidonic acid release in DDT1-MF2 cells: putative interrelations.

Studies were undertaken in an effort to discern possible mechanisms by which the A1 adenosine receptor agonist cyclopentyladenosine (CPA) enhances the norepinephrine-stimulated (NE-stimulated) hydrolysis of phosphoinositides in DDT1-MF2 cells. Measurements of arachidonic acid release revealed similar behaviours to those observed in measurements of phosphoinositide hydrolysis. In the presence of NE, both second messenger responses were potentiated by the addition of CPA, whereas in the absence of NE, CPA had little or no effect on either second messenger. The stimulation and potentiation of both second messenger responses were enhanced in the presence of extracellular calcium, and in each case these effects were persistent over time. For either second messenger system the stimulation by NE and the potentiation by CPA appeared to utilize separate mechanisms as evidenced by the fact that the potentiations by CPA were selectively antagonized by a cAMP analogue or by pertussis toxin, whereas the stimulations by NE were essentially unaffected by these agents. Inhibition of phospholipase A2 (PLA2) also blocked the potentiation of PLC by CPA, without affecting NE-stimulated phosphoinositide hydrolysis. Furthermore, in the presence of CPA, the exogenous administration of PLA2 was found to stimulate phosphoinositide hydrolysis in these cells. These data are consistent with a hypothesis whereby the apparent potentiation of NE-stimulated phosphoinositide hydrolysis by CPA is actually due to the stimulation by CPA of a second pathway of phospholipase C activity which is additive to that of NE. The activation of PLC and PLA2 by NE produces phospholipid products which may play a permissive role in the pathway coupling adenosine A1 receptors to these phospholipases. The formation of lysophosphatidic acid is suggested as one possible mediator of this permissive effect.

Adenosine↗

PubMed1992

5-HT1C receptors mediate phosphoinositide turnover activation in the immature rat hippocampus.

The activation of phosphoinositide turnover in rat cerebral cortex and choroid plexus is triggered by the stimulation of 5-HT2 and 5-HT1C receptors, respectively. To characterize the 5-HT receptor subtype mediating the activation of phosphoinositide turnover in the hippocampus, the potency of several 5-HT agonists and antagonists on total [3H]inositol phosphate formation has been compared in the hippocampus, cerebral cortex and choroid plexus of immature rats. 5-HT, alpha-methyl-5-HT, quipazine, MK-212, mCPP (m-chlorophenylpiperazine) and TFMPP (m-trifluoromethylphenylpiperazine) are less potent and efficient in stimulating phosphoinositide turnover in the hippocampus and cerebral cortex than in the choroid plexus. However, for a number of 5-HT receptor antagonists (ketanserin, spiperone, ritanserin, pizotifen, cyproheptadine, mesulergine, mianserin, methiothepin, methysergide) there is a good correlation (r = 0.82) between their antagonistic potency in the hippocampus and choroid plexus while such correlation is not observed for the hippocampus and cerebral cortex. The specific 5-HT2 receptor antagonist spiperone only partially antagonizes (37% inhibition at 1 microM) the stimulation by 5-HT of phosphoinositide turnover in the hippocampus. These results suggest that in the immature rat hippocampus the activation of phosphoinositide turnover by 5-HT is mainly mediated by the 5-HT1C receptor subtype.

Animals↗

PubMed1993

Protein kinase C inhibitors potentiate angiotensin II-induced phosphoinositide hydrolysis and intracellular Ca2+ mobilization in renal mesangial cells.

Stimulation of mesangial cells with angiotensin II leads to rapid phosphoinositide hydrolysis and subsequent mobilization of intracellular Ca2+. Previous studies indicated that activation of protein kinase C (PKC) triggers a negative-feedback signal, which limits phosphoinositide turnover. By comparing the relative susceptibility of PKC isoenzymes to phorbol ester-induced down-regulation with the down-regulation of the functional cell response, i.e. feedback inhibition of inositol trisphosphate production, we inferred that PKC-alpha and PKC-delta are candidates for regulating phosphoinositide hydrolysis in mesangial cells. To test this hypothesis further, we examined the effects of inhibitors of PKC, that are reportedly not active on PKC-delta, on angiotensin II-stimulated phosphoinositide degradation and Ca2+ mobilization. Pretreatment of mesangial cells with the PKC inhibitors staurosporine and K252a potently augmented inositol trisphosphate and 1,2-diacylglycerol formation as well as Ca2+ mobilization in response to angiotensin II. These results suggest that PKC-alpha, but not PKC-delta, is the most likely candidate mediating feedback inhibition of angiotensin II-stimulated phosphoinositide turnover in mesangial cells.

Alkaloids↗

PubMed1999

The phosphoinositide 3-kinase/Akt pathway is activated by daunorubicin in human acute myeloid leukemia cell lines.

Daunorubicin induces apoptosis in myeloid leukemia cells by activation of neutral sphingomyelinase and ceramide generation occurring 4-10 min after daunorubicin addition. We show here that daunorubicin is able to increase the phosphoinositide 3-kinase activity and enhance intracellular phosphoinositide 3-kinase lipid products prior to ceramide generation. Daunorubicin activates Akt, a downstream phosphoinositide 3-kinase effector. Interestingly, the phosphoinositide 3-kinase inhibitors wortmannin and LY294002 accelerate daunorubicin-induced apoptosis in U937 cells. The phosphoinositide 3-kinase/Akt pathway has been involved in cell survival following serum deprivation, tumor necrosis factor alpha, anti-Fas and UV radiations. Our results suggest that anti-tumor agents such as daunorubicin may also activate anti-apoptotic signals that could contribute to drug resistance.

Acute Disease↗

PubMed1991

Muscarinic receptor stimulation of phosphoinositide hydrolysis in the human isolated urinary bladder.

The stimulatory action of carbachol and acetylcholine (ACh) on phosphoinositide turnover, as well as their contractile effects, were investigated in human isolated detrusor muscle. Carbachol, and ACh in combination with 10(-7) M physostigmine, induced increases in phosphoinositide turnover. However, at all the concentrations tested, carbachol was more effective than ACh (plus physostigmine), and at the highest concentration used (10(-4) M), the difference was significant (p less than 0.05). Also in a Ca(2+)-free medium containing the chelator EGTA (10(-4) M), both agonists (10(-4) M) induced small but distinct increases in phosphoinositide breakdown. Carbachol and ACh contracted the detrusor preparations concentration-dependently, and the responses were almost identical when ACh was combined with 10(-7) M physostigmine. In Ca(2+)-free medium the agonists elicited a moderate but concentration-dependent contractile response at high concentrations. The results show that muscarinic receptor agonists stimulate phosphoinositide turnover in the human bladder. Possibly, this effect is coupled to multiple muscarinic receptor subtypes. More studies are required to elucidate to what extent phosphoinositide breakdown participates in the contractile activation of this tissue.

Acetylcholine↗

PubMed2002

5-HT2A receptor-stimulated phosphoinositide hydrolysis in the stimulus effects of hallucinogens.

The role of 5-HT2A-mediated stimulation of phosphoinositide hydrolysis in the discriminative effects of hallucinogens was investigated in PC12 cells stably expressing the rat 5-HT2A receptor (PC12-5-HT2A cells). The hallucinogenic compounds, D-lysergic acid diethylamide (LSD), (-)2,5-dimethoxy-4-methylamphetamine (DOM), psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (MDMT) and N,N-diethyltryptamine (DET), all caused a concentration-dependent increase in the generation of [3H]inositol phosphates. The nonhallucinogenic compounds, 6-fluoro-N,N-diethyltryptamine (6-F-DET), lisuride and quipazine, also displayed significant efficacy in stimulating phosphoinositide hydrolysis, while 2-bromo-lysergic acid diethylamide (BOL), which is not a hallucinogen, did not alter inositol phosphate generation. The beta-carbolines, harmaline and harmane, also did not alter phosphoinositide hydrolysis. Comparison of these results with previous drug discrimination studies indicated the apparent lack of correlation between the degree of substitution in LSD- and DOM-trained animals and efficacy in stimulating phosphoinositide hydrolysis. The present study indicates that 5-HT2A-mediated stimulation of phosphoinositide hydrolysis does not appear to be the sole critical signaling mechanism involved in the discriminative effects of hallucinogens.

Animals↗

PubMed1998

Glutathione depletion exacerbates impairment by oxidative stress of phosphoinositide hydrolysis, AP-1, and NF-kappaB activation by cholinergic stimulation.

Oxidative stress appears to contribute to neuronal dysfunction associated with Alzheimer's disease and other CNS neurodegenerative disorders. This investigation examined if oxidative stress might contribute to impairments in cholinergic receptor-linked signaling systems and if intracellular glutathione levels modulated responses to oxidative stress. To do this the activation of the AP-1 and NF-kappaB transcription factors and of the phosphoinositide second-messenger system was measured in human neuroblastoma SH-SY5Y cells after exposure to the oxidants H2O2 or diamide, with or without prior depletion of cellular glutathione. H2O2 concentration-dependently inhibited carbachol-stimulated AP-1 activation and this inhibition was potentiated in glutathione-depleted cells. Carbachol-stimulated NF-kappaB activation was unaffected by H2O2 unless glutathione was depleted, in which case there was a H2O2 concentration-dependent inhibition. Glutathione depletion also potentiated the inhibition by H2O2 of carbachol- or G-protein (NaF)-stimulated phosphoinositide hydrolysis, whereas phospholipase C activated by the calcium ionophore ionomycin was not inhibited. The thiol-oxidizing agent diamide also inhibited phosphoinositide hydrolysis stimulated by carbachol or NaF, and glutathione depletion potentiated the diamide concentration-dependent inhibition. Unlike H2O2, diamide also inhibited ionomycin-stimulated phosphoinositide hydrolysis. Activation of both AP-1 and NF-kappaB stimulated by carbachol was inhibited by diamide, and glutathione depletion potentiated the inhibitory effects of diamide. Thus, diamide inhibited a wider range of signaling processes than did H2O2, but glutathione depletion increased the susceptibility of phosphoinositide hydrolysis and of transcription factor activation to inhibition by both H2O2 and diamide. These results demonstrate that the vulnerability of signaling systems to oxidative stress is influenced by intracellular glutathione levels, indicating that cell-selective susceptibility to inhibition of signal transduction systems by oxidative stress can arise from cellular variations in antioxidant capacity.

Analysis of Variance↗

PubMed2001

Modular phosphoinositide-binding domains--their role in signalling and membrane trafficking.

The membrane phospholipid phosphatidylinositol is the precursor of a family of lipid second-messengers, known as phosphoinositides, which differ in the phosphorylation status of their inositol group. A major advance in understanding phosphoinositide signalling has been the identification of a number of highly conserved modular protein domains whose function appears to be to bind various phosphoinositides. Such 'cut and paste' modules are found in a diverse array of multidomain proteins and recruit their host protein to specific regions in cells via interactions with phosphoinositides. Here, with particular reference to proteins involved in membrane traffic pathways, we discuss recent advances in our understanding of phosphoinositide-binding domains.

Amino Acid Sequence↗

PubMed2002

Nuclear phosphoinositides could bring FYVE alive.

Phosphoinositide signalling systems exist in all eukaryotes. A high degree of evolutionary conservation is found at the functional level, but distinct phylogenetic differences are also becoming evident. Although the nuclear phosphoinositide system is likely to be a primordial forerunner of the plasma membrane system, relatively little is known about it. However, nuclear phosphoinositides might have far more diverse roles than hitherto envisaged and interact specifically with regulatory proteins containing phosphoinositide-binding domains. A novel family of proteins, so far only identified in plants, display domain structures that might link phosphoinositide metabolism to nuclear function in an unexpected way.

Amino Acid Sequence↗