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Stimulatory effect of bombesin on phosphoinositide metabolism in the rat pineal gland.

The pineal gland is under complex peptidergic nervous control originating from hypothalamic nuclei. The daily rhythm of bombesin-like peptide in the hypothalamus suggests that this neuropeptide, similarly as other neuropeptides, might be involved in modulation of the physiological activity of the pineal gland. In our experiments we studied the mechanism of signal transduction of bombesin in the isolated pineal glands of rats. The phosphoinositide signalling system was examined by measuring 32P-labelling of phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP) and phosphatidylinositol bisphosphate (PIP2), which reflects phosphoinositide cycle activation. Bombesin induced a significant increase in 32P-labelling of PI, PIP and PIP2. The antagonist of this neuropeptide, (D-Phe12-Leu14)-bombesin, suppressed the increase in 32P-labelling of all phosphoinositides. Bombesin was without effect on cAMP dependent protein phosphorylation. The data indicate that bombesin activates the PI signalling system via specific receptors.

Amino Acid Sequence↗

Regulation of alpha(1)-adrenoceptor-linked phosphoinositide metabolism in cultured glia: involvement of protein phosphatases and kinases.

Noradrenaline-stimulated phosphoinositide breakdown in cultured glia was found to be mediated by alpha(1A)-adrenoceptors. The alpha(1A)-selective agonist A61603 was as effective as noradrenaline in eliciting 3H-inositol phosphate (IP) accumulation but was approximately 50-fold more potent. In addition, the use of selective antagonists revealed a clear rank order of potency in the ability of these drugs to reverse the effect of noradrenaline on phosphoinositide breakdown: RS17053 (alpha(1A)-selective) >>AH11110A (alpha(1B)-selective)>BMY7378 (alpha(1D)-selective). Pre-treatment of cultured glia with the protein phosphatase inhibitor okadaic acid resulted in a concentration- and time-dependent reduction in noradrenaline-evoked 3H-IP accumulation. This effect was mimicked by, but was not additive with, a phorbol ester, was reversed by protein kinase C (PKC) inhibitors and was not evident in cells which had been PKC depleted. The ability of cell extracts to dephosphorylate radiolabelled glycogen phosphorylase revealed the presence of the phosphatases PP1 and PP2A in almost equal abundance. Okadaic acid pre-treatment of intact cultures elicited a marked reduction in total phosphatase activity, particularly that mediated by PP2A. We also determined the effect of okadaic acid pre-treatment on PKC and cyclic AMP-dependent protein kinase (PKA) activities in these cells. PKC and PKA activities in cell extracts were assessed by determining the incorporation of 32P into histone and kemptide, respectively. Okadaic acid elicited increases in both Ca(2+)-dependent and Ca(2+)-independent PKC activity; in addition, increases in both initial and total PKA activities were also recorded. The effect of okadaic acid on noradrenaline-stimulated 3H-IP accumulation were not, however, mimicked by either forskolin or 8-bromo-cyclic AMP, suggesting that this event is not regulated by PKA. Our data point to roles for both PKC and PP2A in the regulation of alpha(1A)-adrenoceptor-linked phosphoinositide metabolism in cultured cortical glia.

Adrenergic alpha-Agonists↗

The sulphydryl oxidizing reagent diamide affects phosphoinositide-mediated signal transduction: implications for the pathogenesis of Alzheimer's disease.

In fura-2-labelled human platelets, the thiol oxidising agent diamide decreases the intracellular calcium response to thrombin and serotonin without affecting the basal calcium levels. The effect of diamide on the thrombin response could be prevented by pre-treatment with dithiothreitol (DTT) and reduced when DTT was added 60 s after diamide. The effects of diamide and hydrogen peroxide on the thrombin response were additive. Hydrogen peroxide also produced a calcium response per se, but this response was not affected by diamide. Hydrogen peroxide increased rat brain phosphoinositide hydrolysis and reduced the response to carbachol and noradrenaline, whereas diamide was without effect. The binding of [3H]inositol-1,4,5-trisphosphate to human platelet membranes was inhibited by diamide but not by hydrogen peroxide. Thus diamide affects the phosphoinositide signal transduction pathway in a qualitatively different manner from that found with hydrogen peroxide. It is suggested that oxidative stress may contribute to the disturbances in the phosphoinositide transduction pathway that are found in Alzheimer's disease.

Alzheimer Disease↗

Cholesterol-induced growth stimulation, macromolecule synthesis, and increased phosphoinositide metabolism of ascites tumour cells in culture.

Ascites tumour cells have previously been shown by us to require exogenous cholesterol for growth. To investigate further this phenomenon, we have used, in addition to free cholesterol, cholesterol complexed to digitonine, to elaborate the specificity of this growth-controlling process using a chemically defined medium. Our data show that only free cholesterol stimulates cell growth and macromolecule synthesis in a dose-dependent manner, suggesting that the proper embedding of the sterol into the membrane is a prerequisite for its function. Furthermore, studies have been performed on the influence of cholesterol on the phosphoinositide metabolism of our cells, as phosphoinositides furnish important second messenger molecules in the cascade of signal transduction. We could show that cholesterol stimulates a transient release of inositol trisphosphate and other inositol phosphates by inducing the activation of phospholipase C (PLC). PLC activation by a factor of about 3 with phosphatidylinositol 4-phosphate and phosphatidyl inositol 4,5-bisphosphate as substrates could be measured directly by using a partially purified membrane preparation. This enzyme activity was found to be strongly dependent on free Ca2+ ions with optimal concentrations of 100 nM for cholesterol- and 50 nM for cholesterol-digitonide-treated cells. Ca2+ concentration for half-maximum activation, however, was identical under both conditions. Phospholipase C activity could be synergistically increased about 2-fold with 25 microg GTP gammaS in cholesterol-digitonide-treated cells as well, suggesting that the coupling between phospholipase C and the G-protein was not disturbed by the complex. These data demonstrate a functional role of cholesterol on cell growth, macromolecule synthesis, and phosphoinositide metabolism mediating the release of important second messenger molecules.

Animals↗

A role for phosphoinositides in tyrosine phosphorylation of p125 focal adhesion kinase in rat pancreatic acini.

Previous studies have shown that different agonists increase tyrosine phosphorylation of the focal adhesion related proteins p125(FAK), p130(Cas), and paxillin in different cell types and that tyrosine phosphorylation depends on the integrity of the actin cytoskeleton. Because phosphoinositides are important for the maintenance of the cytoskeleton, the role of phosphoinositides in the tyrosine phosphorylation of these proteins in response to occupancy of m3 muscarinic and CCK(A) receptors has been investigated in pancreatic acini. Addition of carbachol or CCK-8 to pancreatic acini resulted in rapid increases in the tyrosine phosphorylation of p125(FAK), p130(Cas), and paxillin. Pretreatment of pancreatic acini with LY294002 or wortmannin resulted in a concentration-dependent inhibition of tyrosine phosphorylation of p125(FAK), p130(Cas), and paxillin stimulated by carbachol or CCK-8. Carbachol- or CCK-8-stimulated tyrosine phosphorylation of these proteins was not inhibited by rapamycin, PD 98059 or SB 203580, and thus it was dissociated from the activation of p70 S6 or MAP kinases. These results indicate that m3 muscarinic and CCK(A) receptor-mediated increase in p125(FAK), p130(Cas), and paxillin tyrosine phosphorylation in pancreatic acini depends on the ability of these cells to synthesise phosphoinositides.

Animals↗

The role of phosphoinositides in membrane transport.

Phosphoinositides serve as intrinsic membrane signals that regulate intracellular membrane trafficking. Recently, phosphoinositides have been found to direct the localization and activity of effector proteins containing consensus sequence motifs such as FYVE, PH and ENTH domains. In addition, recent results show that regulated synthesis and turnover of phosphoinositides by membrane-associated phosphoinoside kinases and phosphatases spatially restrict the location of effectors critical for cellular transport processes, such as clathrin-mediated endocytosis, autophagy, phagocytosis, macropinocytosis and biosynthetic trafficking.

Animals↗

Phosphoinositides and the golgi complex.

Phosphoinositides act as precursors of second messengers and membrane ligands for protein modules. Specific lipid kinases and phosphatases are located and differentially regulated in cell organelles, generating a non-uniform distribution of phosphoinositides. Although it is not clear whether and how the phosphoinositide pools are integrated, it is certain that they locally control fundamental processes, including membrane trafficking. This applies to the Golgi complex, where a direct, central role of the phosphatidylinositol 4,5-bisphosphate precursor phosphatidylinositol 4-phosphate has recently been reported.

Animals↗

Phosphoinositides in membrane traffic.

Phosphoinositides serve as direct local modulators or recruiters of the protein machineries that control membrane trafficking. In the past year, examples of phosphoinositide effectors include regulators of small GTPases in coat assembly, dynamin in clathrin coated vesicle formation and FYVE finger proteins in endocytic membrane traffic. A novel phosphoinositide appears to regulate effectors involved in the formation of multivesicular endosomes.

Animals↗

Contribution of phosphoinositide-dependent signalling to photomotility of Blepharisma ciliate.

The effect of experimental procedures designed to modify an intracellular phosphoinositide signalling pathway, which may be instrumental in the photophobic response of the protozoan ciliate Blepharisma japonicum, has been investigated. To assess this issue, the latency time of the photophobic response and the cell photoresponsiveness have been assayed employing newly developed computerized videorecording and standard macro-photographic methods. Cell incubation with neomycin, heparin and Li+, drugs known to greatly impede phosphoinositide turnover, causes evident dose-dependent changes in cell photomotile behaviour. The strongest effect on photoresponses is exerted by neomycin, a potent inhibitor of polyphosphoinositide hydrolysis. The presence of micromolar concentrations of neomycin in the cell medium causes both prolongation of response latency and decrease of cell photoresponsiveness. Neomycin at higher concentrations (> 10 microM) abolishes the cell response to light at the highest applied intensity. A slightly lower inhibition of cell responsiveness to light stimulation and prolongation of response latency are observed in cells incubated in the presence of heparin, an inositol trisphosphate receptor antagonist. Lithium ions, widely known to deplete the intracellular phosphoinositide pathway intermediate, inositol trisphosphate, added to the cell medium at millimolar level, also cause a slowly developing inhibitory effect on cell photoresponses. Mastoparan, a specific G-protein activator, efficiently mimics the effect of light stimulation. In dark-adapted ciliates, it elicits ciliary reversal with the response latency typical for ciliary reversal during the photophobic response. Sustained treatment of Blepharisma cells with mastoparan also suppresses the photoresponsiveness, as in the case of cell adaptation to light during prolonged illumination. The mastoparan-induced responses can be eliminated by pretreatment of the cells with neomycin. Moreover, using antibodies raised against bovine transducin, a cross-reacting protein with an apparent molecular mass of about 55 kDa in the Blepharisma cortex fraction is detected on immunoblots. The obtained results indirectly suggest that the changes in internal inositol trisphosphate level, possibly elicited by G-protein-coupled phospholipase C, might play a role in the photophobic response of Blepharisma. However, further experiments are necessary to clarify the possible coupling between the G-protein and the putative phospholipase C.

Animals↗

Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains.

Pleckstrin homology (PH) domains are protein modules of around 120 amino acids found in many proteins involved in cellular signaling. Certain PH domains drive signal-dependent membrane recruitment of their host proteins by binding strongly and specifically to lipid second messengers produced by agonist-stimulated phosphoinositide 3-kinases (PI 3-Ks). We describe X-ray crystal structures of two different PH domains bound to Ins(1,3,4,5)P4, the head group of the major PI 3-K product PtdIns(3,4,5)P3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P3 specific, while the other (from DAPP1/PHISH) binds strongly to both PtdIns(3,4,5)P3 and its 5'-dephosphorylation product, PtdIns(3,4)P2. Comparison of the two structures provides an explanation for the distinct phosphoinositide specificities of the two PH domains and allows us to predict the 3-phosphoinositide selectivity of uncharacterized PH domains.

Adaptor Proteins, Signal Transducing↗

The class II phosphoinositide 3-kinase C2alpha is activated by clathrin and regulates clathrin-mediated membrane trafficking.

Phosphoinositides play key regulatory roles in vesicular transport pathways in eukaryotic cells. Clathrin-mediated membrane trafficking has been shown to require phosphoinositides, but little is known about the enzyme(s) responsible for their formation. Here we report that clathrin functions as an adaptor for the class II PI 3-kinase C2alpha (PI3K-C2alpha), binding to its N-terminal region and stimulating its catalytic activity, especially toward phosphorylated inositide substrates. Further, we show that endogenous PI3K-C2alpha is localized in coated pits and that exogenous expression affects clathrin-mediated endocytosis and sorting in the trans-Golgi network. These findings provide a mechanistic basis for localized inositide generation at sites of clathrin-coated bud formation, which, with recruitment of inositide binding proteins and subsequent synaptojanin-mediated phosphoinositide hydrolysis, may regulate coated vesicle formation and uncoating.

Amino Acid Sequence↗

Phosphoinositides, key molecules for regulation of actin cytoskeletal organization and membrane traffic from the plasma membrane.

Phosphoinositide plays a critical role not only in generating second messengers, such as inositol 1,4,5-trisphosphate and diacylglycerol, but also in modulating a variety of cellular functions including cytoskeletal organization and membrane trafficking. Many inositol lipid kinases and phosphatases appear to regulate the concentration of a variety of phosphoinositides in a specific area, thereby inducing spatial and temporal changes in their availability. For example, local concentration changes in phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) in response to extracellular stimuli cause the reorganization of actin filaments and a change in cell shape. PI(4,5)P(2) uncaps the barbed end of actin filaments and increases actin nucleation by modulating a variety of actin regulatory proteins, leading to de novo actin polymerization. PI(4,5)P(2) also plays a key role in membrane trafficking processes. In endocytosis, PI(4,5)P(2) targets clathrin-associated proteins to endocytic vesicles, leading to clathrin-coated pit formation. On the contrary, PI(4,5)P(2) must be dephosphorylated when they shed clathrin coats to fuse endosome. Thus, through regulating actin cytoskeleton organization and membrane trafficking, phosphoinositides play crucial roles in a variety of cell functions such as growth, polarity, movement, and pattern formation.

Actin Cytoskeleton↗

Full-contact domain labeling: identification of a novel phosphoinositide binding site on gelsolin that requires the complete protein.

Gelsolin, an actin and phosphoinositide binding protein, was photoaffinity labeled using a variety of benzophenone-containing phosphoinositide polyphosphate analogues. The N-terminal half and the C-terminal half of gelsolin showed synergy in the binding of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. Competitive displacement experiments with dibutyryl, dioctanoyl, or dipalmitoyl derivatives of PtdIns(4,5)P(2) suggested that, in addition to the inositol headgroup, a diacylglyceryl moiety was important for binding; these analogues also inhibited the gelsolin-severing activity of F-actin. In addition to the previously identified PtdIns(4,5)P2 binding site in the N-terminal half of gelsolin, a new binding site was identified in the C-terminal half by mapping the photocovalently modified peptide fragments. Moreover, increasing concentrations of Ca(2+) decreased the binding of the photolabile analogues to the C-terminal phosphoinositide binding site on gelsolin. A molecular model of the binding of PtdIns(4,5)P2 within two folded repeats of gelsolin has been calculated using these data.

Actins↗

Isolation and characterization of one soluble and two membrane-associated forms of phosphoinositide-specific phospholipase C from human platelets.

Two forms (mPLC-I, mPLC-II) of phosphoinositide-specific phospholipase C have been purified, 1494- and 1635-fold, respectively, from plasma membranes of human platelets. Purified mPLC-I and mPLC-II had estimated molecular weights by gel filtration and sodium dodecyl sulfate-polyacrylamide gels of 69,000 and 63,000, respectively. Two cytosolic forms (PLC-I and PLC-II) of phosphoinositide-specific phospholipase C were also resolved on a phenyl-Sepharose column. The major cytosolic form present in outdated platelets, PLC-II, was purified to homogeneity by chromatography on Fast Q-Sepharose, cellulose phosphate, heparin-agarose, phenyl-Sepharose, Superose 12, DEAE-5PW, and hydroxylapatite. Purified PLC-II had a molecular weight of 57,000 on sodium dodecyl sulfate-polyacrylamide gels. mPLC-I, mPLC-II, and PLC-II hydrolyzed both PI and PIP2. The Vmax for PIP2 hydrolysis was similar for all three forms of PLC and was approximately 5-fold greater than for PI hydrolysis. The Km for PIP2 hydrolysis was also similar for the three enzymes. In contrast, the Km for PI hydrolysis by PLC-II was 10-fold lower than by mPLC-I and mPLC-II. In addition, antibody prepared against PLC-II did not cross-react with either mPLC-I or mPLC-II. These data indicate that platelets contain membrane-associated phosphoinositide-specific phospholipases C that are distinct from at least one cytosolic form (PLC-II) of the enzyme.

Blood Platelets↗

Purification and characterization of bovine heart phosphoinositide-specific phospholipase C: kinetic analysis of the Ca2+ requirement and La3+ inhibition.

Bovine heart contains multiple phosphoinositide-specific phospholipase C (PIC) activities separable by ion-exchange chromatography. One PIC activity was purified to apparent homogeneity and migrated as a single band of Mr 85,000 on SDS-PAGE. The purified PIC was characterized with sonicated suspensions of either pure phosphatidylinositol 4,5-bisphosphate (PIP2) or phosphatidylinositol (PI) as substrates. At pH 7, apparent Vmax and Km values were higher for PIP2 than for PI, but the value of Vmax/Km was similar for the two substrates. PIC required Ca2+ for the hydrolysis of either PI or PIP2, and increasing free Ca2+ concentrations from 20 to 300 nM saturated PIC activity. The requirement of Ca2+ for PIC activity and the sensitivity of PIC to Ca2+ concentrations in the physiological range suggested the ion may be a cofactor. The PIC reaction mechanism was determined by two-substrate kinetic analysis; the data fit a model in which PIC contained single sites for Ca2+ and phosphoinositide, and utilized a rapid-equilibrium, random-order ternary mechanism for phosphoinositide hydrolysis. The KCa value for either PI or PIP2 hydrolysis was approximately 30 nM, suggesting resting intracellular free Ca2+ concentrations are sufficient to saturate the Ca2+ site of PIC. La3+ was used as a calcium analogue to modulate PIC activity. Low concentrations of LaCl3 (0.01-0.3 microM) inhibited PIC activity competitively with respect to calcium, consistent with a Ca2+ binding site on the enzyme.

Animals↗

Phosphoinositide synthesis in bovine rod outer segments.

Phosphoinositide turnover has been implicated in signal transduction in a variety of cells, including photoreceptors. We demonstrate here the presence of a complete pathway for rapid synthesis of phosphoinositides in isolated bovine retinal rod outer segments (ROS) free of microsomal contaminants. Synthesis was measured by the incorporation of label from radioactive precursors, [gamma-32P]ATP and [3H]inositol. [gamma-32P]ATP also produced large amounts of labeled phosphatidic acid. Incorporation of [3H]inositol required CTP and Mn2+. Mn2+ increased 32P incorporation into phosphatidylinositol 4-phosphate, while spermine increased phosphoinositide labeling generally. ROS that had been washed to remove soluble and peripheral proteins incorporated less label than unwashed ROS into phosphatidic acid and phosphatidylinositol. No effects of light were detected. Inhibitory effects of high concentrations of nonhydrolyzable GTP analogues were probably due to competition with ATP.

Adenosine Triphosphate↗

NMR structure of the amino-terminal domain from the Tfb1 subunit of TFIIH and characterization of its phosphoinositide and VP16 binding sites.

General transcription factor IIH (TFIIH) is recruited to the preinitiation complex (PIC) through direct interactions between its p62 (Tfb1) subunit and the carboxyl-terminal domain of TFIIEalpha. TFIIH has also been shown to interact with a number of transcriptional activator proteins through interactions with the same p62 (Tfb1) subunit. We have determined the NMR solution structure of the amino-terminal domain from the Tfb1 subunit of yeast TFIIH (Tfb1(1-115)). Like the corresponding domain from the human p62 protein, Tfb1(1-115) contains a PH domain fold despite a low level of sequence identity between the two functionally homologous proteins. In addition, we have performed in vitro binding studies that demonstrate that the PH domains of Tfb1 and p62 specifically bind to monophosphorylated inositides [PtdIns(5)P and PtdIns(3)P]. NMR chemical shift mapping demonstrated that the PtdIns(5)P binding site on Tfb1 (p62) is located in the basic pocket formed by beta-strands beta5-beta7 of the PH domain fold. Interestingly, the structural composition of the PtdIns(5)P binding site is different from the composition of the binding sites for phosphoinositides on prototypic PH domains. We have also determined that the PH domains from Tfb1 and p62 are sufficient for binding to the activation domain of VP16. NMR chemical shift mapping demonstrated that the VP16 binding site within the PH domain of Tfb1 (p62) overlaps with the PtdIns(5)P binding site on Tfb1 (p62). These results provide new information about the recognition of phosphoinositides by PH domains, and point to a potential role for phosphoinositides in VP16 regulation.

Binding Sites↗

An endogenous Na+, K+-ATPase inhibitor enhances phosphoinositide hydrolysis in neonatal but not in adult rat brain cortex.

The effect of an endogenous Na+, K+-ATPase inhibitor, termed endobain E, on phosphoinositide hydrolysis was studied in rat brain cortical prisms and compared with that of ouabain. As already shown for ouabain, a transient effect was obtained with endobain E; maximal accumulation of inositol phosphates induced by endobain E was 604 +/- 138% and 186 +/- 48% of basal values in neonatal and adult rats, respectively. The concentration-response plot for the interaction between endobain E and phosphoinositide turnover differed from that of ouabain, thus suggesting the involvement of distinct mechanisms. In the presence of endobain E plus ouabain at saturating concentrations, no additive effect was recorded, suggesting that both substances share at least a common step in their activation mechanism of inositol phosphates metabolism or that they enhance phosphatidylinositol 4,5-biphosphate breakdown from the same membrane precursor pool, until its exhaustion. Experiments with benzamil, a potent blocker of Na+/Ca2+ exchanger, showed that it partially and dose-dependently inhibited endobain E effect. These results indicate that the endogenous Na+, K+-ATPase inhibitor endobain E, like ouabain, is able to stimulate phosphoinositide turnover transiently during postnatal brain development.

Aging↗