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PubMedDate not supplied

[The role of membrane phosphoinositides in mediating hormonal effects].

The present notions on the pathways of phosphoinositide metabolism in a cell and on the functional significance of the given process are reported. The enzymic systems providing catabolism of phosphoinositides are analyzed. The data indicating the dose interrelation between the stimulation of the phosphatidyl inosite and polyphosphoinositides metabolism by hormones and the Ca2+ transport into a cell are generalized. Universality, biochemical mechanisms and functional significance of the "phosphatidyl inosite" response are discussed. The phosphoinositide metabolism is considered from the standpoint of its significance for other cell processes: synthesis of eicosanoids, provision of Ca2+-dependent processes in the synapse, cell proliferation, activation and the "anchoring" of enzymes on membranes.

Animals↗

PubMed1986

Carbachol- and norepinephrine-stimulated phosphoinositide metabolism in rat brain: effect of chronic cholinesterase inhibition.

Activation of cholinergic muscarinic receptors leads to several biochemical events including an increased turnover of phosphoinositides. In this study we have investigated whether repeated administration of the organophosphorus insecticide disulfoton, known to cause the development of tolerance to this compound, would affect phosphoinositide metabolism in rat brain. Basal and carbachol-stimulated phosphoinositide metabolism were measured in cerebral cortex slices, by measuring the accumulation of inositol phosphates (InsPs) in the presence of lithium. In control animals carbachol caused a 600% increase in InsPs accumulation with an EC50 of 100 microM. Maximal effect occurred with a LiCl concentration of 7.5 mM and required the presence of calcium. Administration of disulfoton for 10 days (2 mg/kg/day by gavage), decreased the number of muscarinic receptors in cortex from 1.1 to 0.7 pmol/mg of protein without changing the affinity of the receptors (both measured by binding of [3H]quinuclidinyl benzilate). Acetylcholinesterase was inhibited by 85%. Basal InsPs accumulation was unchanged in disulfoton-treated rats, whereas carbachol-stimulated InsPs accumulation decreased by 18%. No changes of norepinephrine-stimulated InsPs formation and of alpha-1 adrenoceptors were present in cortices from disulfoton-treated rats. Recovery of muscarinic receptor binding and carbachol-stimulated InsPs accumulation occurred at a similar rate and was completed 2 to 3 weeks after the end of the treatment, whereas acetylcholinesterase activity was still 38% inhibited 3 weeks later. These results support the hypothesis that a functional adaptation of muscarinic receptors is involved in the development of tolerance to organophosphates.

Acetylcholinesterase↗

PubMed1987

Comparison of norepinephrine- and veratrine-induced phosphoinositide hydrolysis in rat brain.

Stimulation of phosphoinositide hydrolysis by depolarization with veratrine was compared to that produced by stimulation of alpha-1 adrenoceptors by norepinephrine. The phosphoinositides in rat cerebral cortex were labeled with [myo-3H]inositol and the effects of the drugs on the formation of the following inositol phosphates were determined: inositol 1-phosphate (IP); inositol 1,4-bisphosphate (IP2); mixture of inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate (IP3). Termination of the hydrolysis by trichloroacetic acid resulted in lower basal levels and more reproducible results than termination by water lysis or a chloroform-methanol mixture (CHCl3-MeOH). The amounts of IP and IP2 formed by a maximal concentration of veratrine were about one half of that formed by a maximal concentration of norepinephrine although the amount of IP3 formed after stimulation by veratrine was only about 10% of that produced by norepinephrine. The increase in IP was linear with time (30 min) for both norepinephrine and veratrine. Stimulation of IP2 and IP3 formation by veratrine reached a maximum at 5 min whereas that produced by norepinephrine continued to increase for 30 min. Blockade of voltage-dependent calcium channels with manganese produced nearly complete antagonism of the veratrine response while only partially antagonizing the norepinephrine response. Norepinephrine-induced IP2 formation was less sensitive to manganese than was formation of IP or IP3. These data suggest that either veratrine and norepinephrine cause hydrolysis of different pools of phosphoinositide or that the hydrolysis occurs by different mechanisms. The data also suggest that IP and IP2 may be produced directly from phosphatidylinositol and phosphatidylinositol 4-phosphate rather than solely as a metabolite of IP3.

Animals↗

PubMed1994

Mechanical stretch increases proto-oncogene expression and phosphoinositide turnover in vascular smooth muscle cells.

OBJECTIVE: To determine whether changes in haemodynamic load, simulated in vitro by mechanically stretching cultured vascular smooth muscle cells, could be transduced into biochemical signals similar to those produced by growth factors. DESIGN: A system was developed which was capable of stretching cultured vascular smooth muscle cells from 0 to 20%. The effect of stretching quiescent vascular smooth muscle cells on both c-fos messenger RNA (mRNA) expression and release of total inositol phosphates was determined over a time interval of 0-360 min. METHODS: Rat mesenteric artery vascular smooth muscle cells were grown using standard cell culture methods. Induction of the proto-oncogene, c-fos, was determined by Northern blotting. Phosphoinositide breakdown was assessed by measuring [3H]-inositol phosphates released from prelabelled cells. RESULTS: A 20% fixed stretch resulted in a rapid induction of c-fos mRNA which reached maximal levels by 15 min. The amount of c-fos mRNA detected was dependent on the degree of stretch, with maximum induction obtained for 15 and 20% stretch. The effects of mechanical stretch were also assessed on phosphoinositide turnover by measuring [3H]-inositol phosphates released from prelabelled cells. A 20% fixed stretch of vascular smooth muscle cells for 20 min resulted in a 3.2-fold increase in total [3H]-inositol phosphates released compared with unstretched cells. CONCLUSIONS: Our results show that mechanical stretch increases proto-oncogene expression and phosphoinositide turnover in vascular smooth muscle cells in vitro. These observations suggest that mechanical stretch and growth factors share common signal transduction pathways which may be important in the development of vascular hypertrophy.

Animals↗

PubMedDate not supplied

[Method for fractionating phosphoinositides on a thin layer of silica gel].

A procedure is described for fractionation of phosphoinositides using silica gel thin layer chromatography. The procedure may be used in routine studies as this makes it possible to isolate phosphoinositides by using only one system of solvents. The evidence for isolation of phosphoinositide fractions is discussed.

Animals↗

PubMedDate not supplied

[Effect of estradiol on the rat brain synaptosomal phosphoinositide composition].

The in vivo action of estradiol was shown to cause changes both in the total amount of phosphoinsitides and their individual fractions of rat synaptosomes. The maximum elevated levels of phosphoinositides was revealed on 1-hour exposure to the hormone. It is suggested the redistribution of phosphoinositides at the primary stage (1 hour postinjection) of exposure may rely on the initiation and functioning of the phosphoinositide mechanism, the ratio of triphosphoinositide to monophosphoinositide may be a peculiar indicator of the status of synaptosomal membranes for the functioning of this regulatory system.

Animals↗

PubMed1996

Nuclear phosphoinositide-specific phospholipase C, phosphatidylinositol 4,5-bisphosphate and protein kinase C during rat spermatogenesis.

Presence and intracellular distribution of phosphoinositide-specific phospholipase C, phosphatidylinositol 4,5-bisphosphate and protein kinase C have been investigated in rat maturing germ cells and spermatozoa. The isoforms beta 1 and gamma 1 of phosphoinositide-specific phospholipase C were immunologically identified and found to be predominantly nuclear or cytoplasmic and nuclear, respectively. The two enzymes were present in the maturing cell lineage of the seminiferous tubule, except for the nucleus of late spermatids, and absent in spermatozoa, in which, however, a phosphoinositide-specific phospholipase C activity persisted, due to yet uncharacterized enzyme(s). Protein kinase C paralleled these developmental changes, and was completely down-regulated in both total cell homogenates and isolated nuclei obtained from spermatozoa. On the contrary, phosphatidylinositol 4,5-bisphosphate, present at the nuclear level in all cell types, accumulated in the nuclei of late spermatids and spermatozoa. These data support the contention that the spermatozoon nucleus stores a lipid-dependent signaling apparatus which could be reactivated either during sperm maturation or at fertilization.

Animals↗

PubMed1997

A peptide with unique receptor specificity: stimulation of phosphoinositide hydrolysis and induction of superoxide generation in human neutrophils.

Previously, we identified peptides that stimulate phosphoinositide hydrolysis in several leukocyte cell lines from mixtures of random hexapeptide sequences. Moreover, the peptides activate phospholipase C via a pertussis toxin-sensitive G protein-coupled receptor. We now investigate the structure-activity relationship of the peptides with the goal of improving the activity of the peptides, as well as the biologic function of the peptides. Substitution of the L-methionine at the C terminus of peptides with D-methionine markedly increased the effectiveness of the peptides. The half-maximal effective concentrations of MKYMPm-NH2 and WKYMVm-NH2 for stimulation of phosphoinositide hydrolysis in U266 cells were 30 and 0.5 nM, respectively. By BIAcore analysis we confirmed the existence of a receptor for WKYMVm-NH2. Furthermore, the intracellular calcium concentration increase induced by WKYMVm-NH2 was not inhibited by several chemoattractants (FMLP, IL-8, platelet-activating factor, C5a, granulocyte-macrophage CSF, and granulocyte CSF) suggests that WKYMVm-NH2 has a unique cell surface receptor on leukocytes. WKYMVm-NH2 stimulated the phosphoinositide hydrolysis in U937, HL60, and U266 cells, as well as in human neutrophils. Moreover, WKYMVm-NH2 is more effective than FMLP in the production of superoxide in human neutrophils. The data suggest that WKYMVm-NH2 may have the ability to activate the microbicidal functions of human neutrophils.

Amino Acids↗

PubMed1997

Effect of chronic ethanol exposure on myocardial phosphoinositide turnover.

The effect of chronic ethanol consumption (2 months) on atrial contractility and the myocardial phosphoinositide signaling system was examined in rat heart. Two months of ethanol consumption was not associated with changes in heart weight-to-body weight ratios; however, developed twitch tension was significantly lower in the ethanol atria compared with the control atria. Cytosolic and membrane-associated phospholipase C activity in atrial and ventricular tissue was measured and ethanol consumption was only associated with changes in ventricular cytosolic phospholipase C activity. When examining alpha(1)-adrenergic stimulated phosphoinositide turnover in [3H]inositol radiolabeled left atria, no differences in phenylephrine (10 microM)-stimulated inositol monophosphate, inositol bisphosphate, inositol trisphosphate, and inositol tetrakisphosphate were found between groups before or at various times after the addition of phenylephrine. It is concluded that short-term ethanol consumption is associated with depressed contractile function, but not the development of hypertrophy or changes in alpha(1)-adrenoreceptor-stimulated phosphoinositide turnover.

Animals↗

PubMed1997

Dependence on intracellular Ca2+ on mass and turnover of phosphoinositides and phosphatidate in human erythrocytes.

Effects of a calcium-load on mass and turnover of phosphoinositides and phosphatidate were investigated in human erythrocytes by short-term labeling with [32P]Pi. The labeling of phosphatidate was accelerated at normal mass by short-term elevation of free intracellular [Ca2+] up to 1 microM and inhibited by the reduction of normal free [Ca2+]. Thus, the labeling of phosphatidate is a Ca2+-regulated process and not only the consequence of a net synthesis of diacylglycerol by other Ca2+-dependent reactions. Persisting elevation of free intracellular [Ca2+] between 1-40 microM induced an increase of the mass of phosphatidylinositol 4-phosphate with a concomitant decrease of the mass of phosphatidylinositol 4,5-bisphosphate. Under these conditions, the normal steady-state turnover of phosphoinositides was not altered by Ca2+, but mass and turnover of phosphatidate continuously rose. The increase in phosphatidate mass by far exceeded the decrease of the mass of phosphoinositides, indicating that phosphatidate was generated to a great extent by hydrolysis of other phospholipids in addition to the action of phosphoinositidase C with subsequent phosphorylation of diacylglycerol to phosphatidate. The results demonstrate that different phospholipid phosphodiesterases of human erythrocytes are activated by Ca2+-concentrations in the microM range as is known from various other cell types. In contrast to current explanations, Ca2+-dependent phospholipid phosphodiesterases of human erythrocytes did not exhibit an unusually low affinity against rising cytosolic Ca2+-concentrations.

Binding Sites↗

PubMed1997

Initiation of the phosphoinositide cycle by parathyroid hormone in synaptosomes.

We studied the effects of parathyroid hormone 10(-9) M) on the contents of mono-, di-, and triglycerides, total phospholipids, and free arachidonic acid in rat brain cortex synaptosomes using [1-(14)C]arachidonic acid at 2, 5, and 10 sec after addition of the hormone. Our data demonstrated the changes in lipid metabolism in synaptosomal membranes which were especially pronounced at 5 sec after addition of parathyroid hormone. Incorporation of 70% of [1-(14)C]arachidonic acid into the phosphoinositide fraction and the progress of changes in lipid metabolite composition suggest that the phosphoinositide cycle is initiated by parathyroid hormone, and the hormonal signal may be subsequently mediated in nerve cells by 1,2-diacylglycerol, a product of the phosphoinositide cycle.

Animals↗

PubMed2001

Membrane-Permeant 3-OH-Phosphorylated Phosphoinositide Derivatives.

A crucial role in the regulation of epithelial chloride secretion is played by the phosphoinositide PtdIns(3,4,5)P3 . Membrane-permeant derivatives of this and other naturally occurring phosphoinositides have been synthesized. These derivatives, which can be bioactivated, were used in investigations on nasal epithelia of patients suffering from cystic fibrosis.

cyclitols↗

PubMed1998

Prolactin stimulation of phosphoinositide metabolism in CHO cells stably expressing the PRL receptor.

PRL receptor (PRL-R) activation by PRL triggers a cascade of intracellular events including homodimerization of the receptor, activation of cytoplasmic receptor-associated tyrosine kinase and tyrosine-phosphorylation of various signal transducers. In CHO cells, transfected with the long form of PRL-R, an increase in [Ca2+]i was observed following PRL stimulation whereas Ca2+ is generally coupled with the phosphoinositide metabolism. In this study, we investigated phosphoinositide involvement in the PRL transduction pathway. We report that PRL induces rapid increases in two novel inositol phospholipids, almost certainly PtdIns(4,5)P2 and PtdIns(3,4,5)P3. Pre-traitment of CHO cells with wortmanin, a specific PtdIns3-kinase inhibitor, considerably reduces the PRL-induced increase in PtdInd(3,4,5)P3, thus suggesting an involvement of this enzyme in the cascade of activation of cytoplasmic kinase proteins. A pathway beginning with the activation of PtdIns3-kinase, phosphorylation of PtdIns(4,5)P2 and rapid synthesis of PtdIns(3,4,5)P3 is proposed. PtIns(3,4,5)P3 may acts as a lipid second messenger, directly or indirectly responsible for some of the multiple cell changes attributed to PRL.

Androstadienes↗

PubMed1999

A Schizosaccharomyces pombe gene, ksg1, that shows structural homology to the human phosphoinositide-dependent protein kinase PDK1, is essential for growth, mating and sporulation.

Fission yeast (Schizosaccharomyces pombe) requires inositol for growth, mating and sporulation. To define putative genes that are involved in the processing and transduction of the inositol signal, mutants that are temperature sensitive for growth and sporulation were selected on a medium containing non-limiting amounts of inositol. Two such mutants (ksg1-208 and ksg1-358) were analyzed, which are impaired in mating and sporulation at 30 degrees C and undergo growth arrest in the G2 phase of the cell cycle at 35 degrees C. The ksg1 gene was isolated by functional complementation. It maps on the left arm of chromosome II and encodes a putative 592-amino acid protein which exhibits good structural homology to a human 3-phosphoinositide-dependent protein kinase (PDK1) and its rat and Drosophila homologues. The two mutants have the same substitution at amino acid position 159: a glycine residue is replaced by glutamic acid. Deletion of the gene is lethal for haploid cells. We propose that ksg1 is involved in one or several phosphoinositide signalling processes that are responsible for control of the life cycle.

3-Phosphoinositide-Dependent Protein Kinases↗

PubMed1990

Glycerol-3-phospho-D-myo-inositol 4-phosphate (Gro-PIP) is an inhibitor of phosphoinositide-specific phospholipase C.

The deacylated forms of the phosphoinositides were used to determine whether the guinea pig uterus phosphoinositide-specific phospholipase C (PI-PLC I, Mr 60,000) required fatty acids at the sn-1 and sn-2 positions for the hydrolysis of the sn-3 phosphodiester bond. L-alpha-Glycerophospho-D-myo-inositol 4-phosphate (Gro-PIP), but not glycerol 3-phosphate (Gro-3-P), L-alpha-glycerophospho-D-myo-inositol (Gro-PI), or L-alpha-glycerophospho-D-myo-inositol 4,5-bisphosphate (Gro-PIP2), inhibited PI-PLC I in a concentration-dependent manner. Assays performed with 10 microM [3H]phosphatidylinositol ([3H]PI), 10 microM [3H]phosphatidylinositol 4-phosphate ([3H]PIP) or 10 microM [3H]phosphatidylinositol 4,5-bisphosphate ([3H]PIP2) as substrates, with increasing [Gro-PIP] revealed an IC50 = 380 microM. Kinetic studies with increasing [3H]PI substrate concentrations in the presence of 100 microM and 300 microM Gro-PIP demonstrated that Gro-PIP exhibited competitive inhibition; Kis = 40 microM. Ca2+ concentrations over the range 1.1 microM to 1 mM did not effect inhibition, suggesting that Gro-PIP inhibition of [3H]PI hydrolysis was calcium-independent. To determine whether Gro-PIP was a substrate, 20 microM and 500 microM [3H]Gro-PIP were incubated with PI-PLC I. Anion-exchange HPLC analysis revealed no [3H]IP2 product formation, indicating that [3H]Gro-PIP was not hydrolyzed. Assays performed with [3H]PI and [3H]PIP substrates in the presence of 500 microM [3H]Gro-PIP revealed approx. 75% less [3H]inositol 1-phosphate ([3H]IP1) and [3H]inositol 1,4-bisphosphate ([3H]IP2) product formation, respectively, indicating that [3H]Gro-PIP inhibited the hydrolysis of the substrates by PI-PLC I. These data suggest that Gro-PIP does not serve as a substrate, and that it inhibits PI-PLC I by competitive inhibition in a Ca2(+)-independent fashion.

Acylation↗

PubMed1989

Insulin does not activate a phosphoinositide-specific phospholipase C in adipocytes.

Phosphoinositide-specific phospholipase C (PI-PLC) activity was determined in homogenates of adipocytes treated with maximal concentrations of insulin. PI-PLC activity measured using exogenous [3H]phosphatidylinositol [( 3H]PI) and exogenous [3H]phosphatidylinositol 4,5-bisphosphate [( 3H]PIP2) was not altered by prior exposure of adipocytes to insulin. It was possible to see oxytocin-induced breakdown of phosphoinositides but no effect of insulin was seen in intact adipocytes.

Adipose Tissue↗

PubMed1991

Ca(2+)- and ATP-dependent reversible inactivation of pancreatic islet phosphoinositide-specific phospholipase C activity.

Phosphoinositide-specific phospholipase C (PI-PLC) activity in whole homogenates of mouse pancreatic islets decreased 60-85% when the homogenates were incubated at 37 degrees C for 1 h in the presence of down to micromolar concentrations of Ca2+. Ca(2+)-induced inactivation was augmented by calmodulin, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate in the presence of ATP-Mg, and by Mg2+. Inactivation was inhibited when ATP was removed and completely abolished by trifluoperazine and EGTA. Inactivation was not affected by the non-phosphorylating ATP analogue, AMP-PCP, GMP-PNP, glucose, Zn2+ or a series of protease inhibitors. These observations suggest that PI-PLC in broken cell preparations of pancreatic islets may be inactivated via phosphorylation by Ca(2+)-calmodulin-stimulated protein kinase and/or protein kinase C. Inactivation of PI-PLC was reversible. Reactivation started after approx. 2 h incubation, when the concentration of ATP in the homogenate was below 0.15 x 10(-6) M. PI-PLC activity returned to values approx. 25% higher than the initial values. PI-PLC inactivation via phosphorylation by the mentioned protein kinases may constitute a feedback control on the phosphoinositide response, attenuating subsequent diacylglycerol formation and/or Ca2+ mobilization by inositol trisphosphate.

Adenosine Triphosphate↗

PubMed1994

Effects of Alzheimer's disease-related beta amyloid protein fragments on enzymes metabolizing phosphoinositides in brain.

Phosphatidylinositol 4-kinase (PI 4-kinase) and phosphatidylinositol 4-phosphate kinase (PIP kinase) were assayed in membranes prepared from samples of human frontal cortex initially frozen at autopsy. PI 4-kinase activity was significantly lower in Alzheimer's disease patients relative to age-matched controls or patients with Parkinson's disease. PIP kinase was not different in Alzheimer's versus age-matched controls. The beta amyloid protein fragment 1-40 inhibited PI 4-kinase activity in assays of control human or rat cortical membranes. Fragments 1-28 and 25-35 could not mimic the effects of fragment 1-40 while a reverse peptide 40-1 was equipotent. The inhibition of PI 4-kinase by fragment 1-40 was competitive with substrate. The beta amyloid protein fragments had diverse effects on phosphoinositide-specific phospholipase C (PI-PLC) as assayed in rat cortical membranes. Low concentrations of fragment 1-40 stimulated, while high concentrations of 1-40 or 40-1 inhibited PI-PLC activity. Fragment 25-35 stimulated PI-PLC nearly 3-fold, while fragment 1-28 had only minor effects on the enzyme. The results suggest alterations in phosphoinositide metabolism in Alzheimer's disease which could affect signal transduction and/or cytoskeletal organization.

1-Phosphatidylinositol 4-Kinase↗