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PubMed1985

The putative M1 muscarinic receptor does not regulate phosphoinositide hydrolysis. Studies with pirenzepine and McN-A343 in chick heart and astrocytoma cells.

Muscarinic receptor activation stimulates phosphoinositide hydrolysis and inhibits cyclic AMP formation in dissociated embryonic chick heart cells. We used this preparation to examine the hypothesis that the putative M1 and M2 receptor subtypes are selectively coupled to these two responses. Atropine blocks the effects of carbachol on cyclic AMP formation and phosphoinositide breakdown with nearly identical KI values (1.9 and 0.8 nM); these values are close to the apparent KD (1.8 nM) of atropine competition for [3H]N-methylscopolamine binding. Pirenzepine blocks the effect of carbachol on cyclic AMP formation with a KI of 48 nM, a value similar to the apparent KD (23 nM) determined in radioligand-binding studies. In contrast, a higher concentration of pirenzepine is needed to inhibit carbachol-stimulated phosphoinositide hydrolysis (KI = 255 nM). Two selective agonists, McN-A343 and AHR 602, inhibit cyclic AMP formation but do not stimulate phosphoinositide hydrolysis in chick heart cells. Muscarinic receptor-mediated phosphoinositide hydrolysis in 1321N1 astrocytoma cells is also insensitive to McN-A343 or AHR 602 and is antagonized only by relatively high concentrations of pirenzepine. The M1 receptor, as previously defined, has high affinity for pirenzepine and is activated by McN-A343. We find that these ligands have greater activity at muscarinic receptors that inhibit cyclic AMP formation than at those that stimulate phosphoinositide hydrolysis. Thus, if different receptor subtypes are associated with these two responses, the M1 receptor regulates cyclic AMP rather than phosphoinositide metabolism. Our data also demonstrate that the chick heart has muscarinic receptors with high affinity for pirenzepine, and thus, in contrast to rat heart, appears to have predominantly M1 receptors.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed1988

Lpr T cell hyporesponsiveness to mitogens linked to deficient receptor-stimulated phosphoinositide hydrolysis.

The T lymphocytes that expand with age in the peripheral lymphoid organs of autoimmune disease-prone mice homozygous for the lpr mutation display deficient activation and proliferation in response to mitogenic lectins or antigen. In the present study, an attempt was made to correlate the deficient agonist-induced proliferation of these lpr T cells with early transmembrane signaling events mediated by receptor-coupled phosphoinositide hydrolysis. lpr T cells were capable of binding the agonistic lectin, phytohemagglutinin, in a normal manner. In addition, they expressed on their surface the antigen-specific T cell receptor-CD3 complex, which is required for T cell activation, albeit at a lower density than that found on congenic +/+ T cells. Furthermore, lpr T cells contained normal levels of the Ca2+- and phospholipid-dependent enzyme, protein kinase C, and the enzyme was translocated from the cytosol to the particulate fraction upon phorbol ester treatment. On the other hand, the lpr T cells displayed a markedly deficient agonist-induced phosphoinositide hydrolysis in comparison with their congenic +/+ counterparts, as indicated by the minimal accumulation of the phosphoinositide-derived second messengers, inositol phosphates and diacylglycerol. The defective step(s) in transmembrane signaling was bypassed by a combination of phorbol ester plus Ca2+ ionophore, which reconstituted proliferative responses of lpr T cells to normal levels, suggesting that: (a) the phosphoinositide signaling pathway plays an obligatory role in T cell activation; and (b) signaling events subsequent to phosphoinositide hydrolysis are, for the most part, intact in lpr T cells. The deficient step(s) in lpr T cell activation precedes, therefore, the generation of phosphoinositide-derived second messengers and could be due to defective function of the T cell receptor-CD3 complex, GTP-binding proteins, and/or phosphoinositide-specific phosphodiesterase. It remains to be determined whether the deficient signaling event(s) in lpr T cells is a direct pathologic consequence of the lpr gene, or rather, reflects the immature status of a normally minor thymic subset that is aberrantly exported and expanded in lpr mice.

Animals↗

PubMed1989

Differences in the metabolism of inositol and phosphoinositides by cultured cells of neuronal and glial origin.

Phosphoinositide and inositol metabolism was compared in glioma (C6), neuroblastoma (N1E-115) and neuroblastoma X glioma hybrid (NG 108-15) cells. All cell lines had similar proportions of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP), and phosphatidylinositol 4,5-bisphosphate (PIP2). Neuroblastoma and hybrid cells had almost identical phospholipid and phosphoinositide compositions and similar activities for the enzymes metabolizing polyphosphoinositides (PI kinase, PIP phosphatase, PIP kinase, PIP2 phosphatase, PIP2 phosphodiesterase). Glioma cells differed by having greater proportions of ethanolamine plasmalogen and sphingomyelin, lower PIP kinase, 3-5-fold higher PIP phosphatase activity and 10-15-fold greater PIP2 phosphodiesterase activity. Higher PIP phosphatase and PIP2 diesterase activities appear to be characteristic of cells of glial origin, since similar activities were found in primary cultures of astroglia. Glioma cells also metabolize inositol differently. In pulse and pulse-chase experiments, glioma cells transported inositol into a much larger water-soluble intracellular pool and maintained a concentration gradient 30-times greater than neuroblastoma cells. Label in intracellular inositol was less than in phosphoinositides in neuroblastoma and exchanged rapidly with extracellular inositol. In glioma, labeling of intracellular inositol greatly exceeded that of phosphoinositides. As a consequence, radioactivity in prelabeled phosphoinositides could not be effectively chased from glioma cells by excess unlabeled inositol. Such differences between cells of neuronal and glial origin suggest different and possibly supportive roles for these two cell types in maintaining functions regulated through phosphoinositide-linked signalling systems in the central nervous system.

1-Phosphatidylinositol 4-Kinase↗

PubMed1995

Phosphoinositide hydrolysis by phospholipase C modulated by multivalent cations La(3+), Al(3+), neomycin, polyamines, and melittin.

Second messenger production from phosphoinositide hydrolysis is regulated by different pathways, such as G-proteins or tyrosine phosphorylation of phosphoinositide phospholipase C (PI-PLC). Another means of altering the activity of PI-PLC is through cation interaction with the phosphoinositide substrate. A variety of organic and inorganic multi-valent cations were examined for their effects on the activity of purified PI-PLC delta. Surprisingly, the cations produced both stimulation and inhibition of PI-PLC catalyzed phosphoinositide hydrolysis, depending on the substrate and the ion to phosphoinositide stoichiometry. These data support the hypothesis that ionic complexes with phosphoinositides may alter their hydrolysis by PI-PLC.

Aluminum↗

PubMed2005

D-3 phosphoinositides of the ciliate Tetrahymena: characterization and study of their regulatory role in lysosomal enzyme secretion.

Phosphatidylinositol 3-phosphate, PtdIns3P, is a phosphoinositide which is implicated in regulating membrane trafficking in both mammalian and yeast cells. It also serves as a precursor for the synthesis of phosphatidylinositol 3,5-bisphosphate, PtdIns3,5P2, a phosphoinositide, the exact functions of which remain unknown. In this report, we show that these two phosphoinositides are constitutive lipid components of the ciliate Tetrahymena. Using HPLC analysis, PtdIns3P and PtdIns3,5P2 were found to comprise 16% and 30-40% of their relevant phosphoinositide pools, respectively. Treatment of Tetrahymena cells with wortmannin (0.1-10 microM) resulted in the depletion of PtdIns3P and PtdIns3,5P2 without any effect on D-4 phosphoinositides. Wortmannin was further used for the investigation of D-3 phosphoinositide involvement in the regulation of lysosomal vesicular trafficking. Incubation of Tetrahymena cells with wortmannin resulted in enhanced secretion of two different lysosomal enzymes without any change in their total activities. Experiments performed with a T. thermophila secretion mutant strain verified that the wortmannin-induced secretion is specific and it is not due to a diversion of lysosomal enzymes to other secretory pathways. Moreover, experiments performed with a phagocytosis-deficient T. thermophila strain showed that a substantial fraction of wortmannin-induced secretion was dependent on the presence of functional phagosomes/phagolysosomes.

Androstadienes↗

PubMed1994

Tyrosine phosphorylation of phospholipase C-gamma 2 is involved in the activation of phosphoinositide hydrolysis by Fc receptors in human neutrophils.

The stimulation of phosphoinositide hydrolysis by a number of agonists (phosphoinositide response) is a ubiquitous transmembrane signalling process for the regulation of several cell functions. Two mechanisms of activation have been identified that involve different phospholipases C: one regulated by G-proteins and another regulated by receptors having an intrinsic tyrosine kinase domain or that stimulate intracellular tyrosine kinase activity. This last mechanism is activated in several immunological cells, including lymphocytes, mastocytes, NK cells and monocytes, in response to agonists that bind antigen receptors, and receptors for IgE and IgG. In the present study, we have investigated the role of tyrosine phosphorylation in the stimulation of phosphoinositide hydrolysis mediated by Fc gamma Rs in human neutrophils. The results demonstrated that: 1) the activation of Fc gamma Rs with insoluble immune complexes (IIC) induced a tyrosine phosphorylation of several proteins that was dose-dependently inhibited by the tyrosine kinase inhibitor, genistein; 2) the activation of Fc gamma Rs caused a stimulation of phosphoinositide hydrolysis measured as [3H]inositol phosphates formation; 3) genistein depressed the activation of phosphoinositide hydrolysis; 4) among the several proteins that became tyrosine phosphorylated upon Fc gamma Rs activation by IIC, one 145 kDa protein was identified as PLC-gamma 2, using a specific antiserum. The phosphorylation of PLC-gamma 2 was completely inhibited by genistein. These results demonstrate that the phosphoinositide response to activation of Fc gamma Rs involves the tyrosine phosphorylation of PLC-gamma 2.

Genistein↗

PubMed1998

Phosphoinositide hydrolysis activated by muscarinic or glutamatergic, but not adrenergic, receptors is impaired in ApoE-deficient mice and by hydrogen peroxide and peroxynitrite.

Apolipoprotein E (apoE)-deficient (knockout) mice, 4 and 12 months old, were used to test if activation of the phosphoinositide signal transduction system coupled with muscarinic, adrenergic, or glutamatergic metabotropic receptors or inhibition by hydrogen peroxide or peroxynitrite was affected by apoE-deficiency in cerebral cortical slices. In 4-month-old apoE knockout mice, glutamatergic metabotropic receptor-stimulated phosphoinositide hydrolysis was 57% lower than age-matched wild-type mice, whereas the responses to muscarinic and adrenergic receptor stimulation were not different from wild-type mice. In 12-month-old mice, the response to glutamatergic metabotropic receptor stimulation remained impaired in apoE knockout mice, and an impairment in phosphoinositide hydrolysis activated by muscarinic receptors (36% decrease), but not by adrenergic receptors, also was evident. Oxidative stress induced by hydrogen peroxide or peroxynitrite inhibited phosphoinositide hydrolysis activated by muscarinic or glutamatergic metabotropic receptors equivalently (41 to 52%) in 4- and 12-month-old wild-type mice. In contrast, these oxidative agents had no effect on phosphoinositide hydrolysis activated by adrenergic receptors. The inhibitory effects of oxidative stress were not enhanced in apoE knockout mice. These results demonstrate that apoE-deficiency and oxidative stress have receptor-selective inhibitory effects on the phosphoinositide signal transduction system. These differential sensitivities to apoE and to oxidative stress may contribute to selective impairments in signaling activity in neurodegenerative conditions associated with apoE isoform-sensitivity or oxidative stress, such as Alzheimer's disease.

Animals↗

PubMed1992

Phosphoinositides and cell growth.

The findings described above illustrate how the src kinase can influence several new pathways of inositol phosphate metabolism, both at the membrane level with the production of novel D-3 phosphoinositides and the activation of PI-3 kinase, and at the cytosolic level by altering the expression of certain inositol polyphosphates, in particular Ins(1,4,5,6)P4. At present, it is difficult to speculate on the role these phenomena play in cellular transformation by src, since the functions of D-3 phosphoinositides and most inositol polyphosphates are unclear. There is evidence, however, that these new pathways of phosphoinositide metabolism occur in response to other types of cellular stimulations besides src transformation. Novel D-3 phosphoinositides are expressed in a variety of nonneoplastic cells, including human platelets treated with thrombin, smooth muscle cells and stimulated neutrophils. In addition, unusual InsP4 isomers such as D/L-Ins(1,4,5,6)P4 are found in chicken erythrocytes, murine macrophages, AR4-2J rat pancreatoma cells and adrenal glomerulosa cells, to name only a few. Recently, associations have been reported between PI-3 kinases and cytoskeletal elements in thrombin- stimulated platelets, and between activated ras proteins in rat liver epithelial cells. The latter discovery is particularly intriguing since GTP-binding proteins such as ras are known to influence cell shape and serve as downstream effector proteins in the signal transduction pathways of numerous growth factor receptors. Thus, one function of novel phosphoinositides and their metabolites may lie at the level of cytoskeletal and cell shape regulation. Clearly, additional roles for phosphoinositides exist in cells besides their traditional use as precursors for the generation of Ins(1,4,5)P3 and diacylglycerol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Role of the phosphoinositide signal system and methylation of phosphatidylethanolamine in the development of long-term post-tetanic potentiation in rats.

High-frequency stimulation eliciting long-term post-tetanic potentiation of neuronal excitation in slices of the rat olfactory cortex was accompanied by changes in the metabolism of phospholipid components of cell membranes. At the first stage of the development of long-term potentiation (10 min after tetanization), there was a reduction in phosphoinositide metabolism. The maintenance phase of the potentiated state (30 min after tetanization) was associated with a three-fold increase in the incorporation of 14C-labeled groups from adenosylmethionine into phosphatidylethanolamine methylation products and with normalization of phosphoinositide metabolism. Sixty minutes after tetanization, when potentiation had decayed, there was activation of phosphoinositide metabolism and the intensity of phosphatidylethanolamine methylation returned to the control level. It is suggested that the phosphoinositide system plays an important role in the induction of long-term potentiation, as well as at the stage of recovery of normal neuronal excitability, while the long-term maintenance phase of elevated neuronal excitability was associated with long-lasting changes in the level of phosphatidylethanolamine methylation. The effect of glutamate receptor agonists on the carbachol-stimulated phosphoinositide response in potentiated slices was found to differ from that in nonpotentiated slices. The development of the long-term potentiated state is thus accompanied by a modulatory action of glutamate on the phosphoinositide response.

Animals↗

PubMed2000

Natural variants of human p85 alpha phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity.

AIMS/HYPOTHESIS: Phosphoinositide 3-kinase (PI 3K) plays a central part in the mediation of insulin-stimulated glucose disposal. No genetic studies of this enzyme in human syndromes of severe insulin resistance have been previously reported. METHODS: Phosphoinositide 3-kinase p85 alpha regulatory subunit cDNA was examined in 20 subjects with syndromes of severe insulin resistance by single strand conformational polymorphism and restriction fragment length polymorphism analyses. Insulin-stimulated phosphoinositide 3-kinase activity and recruitment into phosphotyrosine complexes of variants of p85 alpha were studied in transiently transfected HEK293 cells. Phosphopeptide binding characteristics of wild-type and mutant p85 alpha-GST fusion proteins were examined by surface plasmon resonance. RESULTS: The common p85 alpha variant, Met326I1e, was identified in 9 of the 20 subjects. Functional studies of the Met326Ile variant showed it to have equivalent insulin-stimulated lipid kinase activity and phosphotyrosine recruitment as wild-type p85 alpha. A novel heterozygous mutation, Arg409Gln, was detected in one subject. Within the proband's family, carriers of the mutation had a higher median fasting plasma insulin (218 pmol/l) compared with wild-type relatives (72 mol/l) (n = 8 subjects, p = 0.06). The Arg409Gln p85 alpha subunit was associated with lower insulin-stimulated phosphoinositide 3-kinase activity compared with wild-type (mean reduction 15%, p < 0.05, n = 5). The recruitment of Arg409Gln p85 alpha into phosphotyrosine complexes was not significantly impaired. GST fusion proteins of wild-type and mutant p85 alpha showed identical binding to phosphopeptides in surface plasmon resonance studies. CONCLUSION/INTERPRETATION: Mutations in p85 alpha are uncommon in subjects with syndromes of severe insulin resistance. The Met326Ile p85 alpha variant appears to have no functional effect on the insulin-stimulated phosphoinositide 3-kinase activity. The impaired phosphoinositide 3-kinase activity of the Arg409Gln mutant suggests that it could contribute to the insulin resistance seen in this family.

Adult↗

PubMed1982

Parathyroid hormone stimulation of renal phosphoinositide metabolism is a cyclic nucleotide-independent effect.

The effects of parathyroid hormone (PTH) and cyclic nucleotides on renal phosphoinositide metabolism were studied using cortical tubules isolated from dog kidneys. PTH stimulated the initial rates of 32Pi incorporation into phosphatidylinositol 4'5'-diphosphate, phosphatidylinositol 4'-monophosphate, phosphatidylinositol and phosphatidic acid. PTH also caused a 45-55% increase in the actual tissue levels of these phospholipids by 5 min of incubation. By 30 min of incubation, the levels of 32Pi incorporated were similar in PTH and control flasks, but the actual levels of the phosphoinositides remained elevated, indicating stimulation of their turnover. Additional evidence of increased turnover of phosphatidylinositol was obtained from tubules pre-incubated with myo-[2-3H]inositol. PTH stimulated a rapid short-lived decrement in [3H]phosphatidylinositol while total phosphatidylinositol levels increased, indicating increased turnover rates of phosphatidylinositol. In tubules pre-incubated with [14C]arachidonic acid, indicating utilization of diacylglycerol produced during turnover for resynthesis of phosphatidic acid and phosphoinositides. Cyclic nucleotides and phosphodiesterase inhibition failed to reproduce the effect of PTH on phosphoinositide metabolism. These studies indicate that PTH stimulates renal phosphoinositide metabolism through a mechanism independent of cAMP which results in a net synthesis of the phosphoinositides.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1990

Reduction of Na+ enhances phosphoinositide hydrolysis and differentiates the stimulatory and inhibitory responses to quisqualate in rat brain slices.

The concentration of Na+ in the incubation medium significantly influenced phosphoinositide hydrolysis induced by some, but not all, agonists in rat cerebral cortical slices. Reductions of the Na+ concentration below 120 mM resulted in incremental increases in basal and norepinephrine-stimulated accumulation of [3H]inositol monophosphate in cortical slices that had been prelabelled with [3H]inositol, and maximal responses were obtained with 0 and 5 mM Na+. In contrast, the responses to carbachol and ibotenate were similar in medium containing 120 or 5 mM Na+. In medium with 120 mM Na+, quisqualate has two effects on phosphoinositide hydrolysis in cortical slices, including a relatively weak stimulatory effect and an inhibitory modulation of the stimulation induced by norepinephrine. These two responses to quisqualate were differentially modulated by Na+; in 5 mM compared with 120 mM Na+ the stimulatory response was greatly increased and the inhibitory effect was mostly eliminated. That these were two separate events was confirmed by the use of L-BOAA (beta-N-oxalyl-L-alpha, beta-diaminopropionic acid), which reproduces the inhibitory, but not the stimulatory effect of quisqualate on phosphoinositide hydrolysis. In 5 mM Na+, inhibition by L-BOAA of norepinephrine-stimulated phosphoinositide hydrolysis was completely eliminated. These results demonstrate that a physiological concentration of Na+ maintains phosphoinositide hydrolysis at a submaximal level of sensitivity to some, but not all, agonists. The differential effects of Na+ on the stimulatory and inhibitory effects of quisqualate further substantiate the suggestion that these are two separate processes and indicate that alterations of the Na+ concentration may influence the effects of quisqualate, and other agonists, on phosphoinositide hydrolysis.

Animals↗

PubMed1995

Developmental switch in the hippocampal serotonin receptor linked to phosphoinositide hydrolysis.

5-HT2A and 5-HT2C receptors couple to the phosphoinositide hydrolysis signal transduction pathway. The present pharmacological analyses provide evidence for a switch in the functional 5-HT receptor in rat hippocampus (from 5-HT2A to 5-HT2C) between the first and third weeks of life. Spiperone and MDL 100,507, antagonists that bind with 300- to 1000-fold higher affinity to 5-HT2A receptors, blocked 5-HT-induced phosphoinositide hydrolysis in hippocampi of 7-day-old, but not 21-day-old, rats. In contrast, the non-selective 5-HT2A/2C receptor antagonists, mesulergine and mianserin, blocked 5-HT-mediated phosphoinositide hydrolysis in both 7- and 21-day-old rats. These results suggest that the 5-HT-induced phosphoinositide hydrolysis signal in hippocampus of 7-day-old rats is mediated predominantly by 5-HT2A receptors, while in 21-day-old rats the phosphoinositide hydrolysis signal is mediated in large part by 5-HT2C receptors. Neither 5-HT2A or 5-HT2C receptor mRNA nor the binding site densities of the two receptors were altered between the two ages, ruling out developmental changes in receptor density as an explanation for the observed differences. We conclude therefore that the hippocampal 5-HT receptor that links to phosphoinositide hydrolysis switches during postnatal development of rats, perhaps reflecting differences in the coupling of 5-HT2A and 5-HT2C receptors to intracellular effector molecules.

Age Factors↗

PubMed1995

Enhancement of 5-hydroxytryptamine-stimulated phosphoinositide hydrolysis in the rat cerebral cortex by repeated immobilization stress.

The present study was undertaken to investigate the influence of repeated immobilization stress on phosphoinositide hydrolysis induced by 5-hydroxytryptamine (5-HT) and noradrenaline in the rat cerebral cortex. Three groups of rats subjected to stress intervention were immobilized for 2 h per day for 3, 7, and 14 days. The stress intervention of any duration did not alter noradrenaline-stimulated phosphoinositide hydrolysis. The 3- and 7-day repeated immobilization enhanced 5-HT-stimulated phosphoinositide hydrolysis, whereas the characteristics of 5-HT2 receptor binding did not change. Chronic treatment with imipramine partially, but significantly, suppressed the increase in 5-HT-stimulated phosphoinositide hydrolysis, induced by the 3-day repeated immobilization. These findings imply that modulation of 5-HT-stimulated phosphoinositide hydrolysis occurs in stressful situations and that the therapeutic effects of tricyclic antidepressant drugs might be related to the modulation of phosphoinositide hydrolysis mediated by 5-HT receptors.

Animals↗

PubMed1984

Differential effects of phenylmethanesulfonyl fluoride (PMSF) on carbachol and potassium stimulated phosphoinositide turnover and contraction in longitudinal smooth muscle of guinea pig ileum.

Phenylmethanesulfonyl fluoride (PMSF) (2 mM), a putative inhibitor of phosphatidylinositol-specific phospholipase C, almost completely inhibited carbachol-stimulated inositol incorporation into phosphatidylinositol (PI) of longitudinal smooth muscle of guinea pig ileum, while it had no effect on potassium-stimulated inositol incorporation. This suggests that the two stimuli may affect phosphoinositide turnover by different mechanisms, distinguishable by PMSF. In contrast to its specific inhibition of carbachol-stimulated phosphoinositide turnover, PMSF produced a transient inhibition of contraction by both carbachol and potassium. The non-selective effect of PMSF on contraction suggests that it is not the result of its inhibitory effect on phosphoinositide breakdown. PMSF (2 mM) inhibited carbachol-stimulated inositol phosphate accumulation in the presence of Li+ by only 15%-19%, indicating that PMSF inhibition of phosphoinositide turnover was not due to its inhibition of phosphoinositide phosphodiesterase, but to one or more steps following phosphoinositide breakdown.

Animals↗

PubMed1991

Regional development of carbachol-, glutamate-, norepinephrine-, and serotonin-stimulated phosphoinositide metabolism in rat brain.

Phosphoinositide metabolism stimulated by activation of cholinergic muscarinic, glutamatergic, alpha-adrenergic and serotoninergic receptors was measured in brain regions of the developing rats. Accumulation of [3H]inositol phosphates ([3H]InsPs) in [3H]inositol-prelabeled slices from cerebral cortex, hippocampus, brainstem and cerebellum was measured as an index of phosphoinositide metabolism. Large age-, neurotransmitter receptor-, and brain region-dependent differences were found. Carbachol-stimulated [3H]InsPs accumulation peaked on postnatal day 7 in cerebral cortex and hippocampus while in cerebellum and brainstem the effect of muscarinic stimulation was maximal at birth and then declined to adulthood. The effect of glutamate also showed a peak on day 7 in hippocampus and brainstem and a developmentally related decrease in cerebral cortex. In the cerebellum, on the other hand, the response to glutamate remained sustained through adulthood. Stimulation of phosphoinositide metabolism by norepinephrine increased with age in hippocampus and cerebral cortex, but decreased in the cerebellum, while the effect of serotonin did not change significantly with age except in cerebellum. These changes in receptor-stimulated phosphoinositide metabolism do not parallel, for the most part, the ontogeny of receptor recognition sites. Activation of the phosphoinositide metabolism pathway leads to an increase in intracellular calcium levels and to stimulation of protein kinase C, which are believed to play significant roles in cellular proliferation and differentiation. Thus, the differential ability of neurotransmitters to stimulate phosphoinositide hydrolysis might play a role in the development of brain regions.

Acetylcholine↗

PubMed1995

Influence of hexachlorocyclohexane on phosphoinositides in rat erythrocyte membranes and brain.

Single exposure of rats to hexachlorocyclohexane (100 mg/kg) did not cause any significant change in phosphoinositide levels in rat erythrocyte membrane and cerebrum (fore brain) 2 or 24 h after exposure. However, the phosphoinositide turnover and generation of second messengers from phosphoinositides were increased in the treated erythrocyte membranes as judged from a marked increase in the incorporation of [2-3H]inositol into phosphoinositides 24 h after the treatment. A significant decrease in phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2) was observed in the erythrocyte membrane and cerebrum of rats repeatedly exposed to the pesticide for 3 or 6 months. This drastic reduction in phosphoinositide levels suggests adverse effects on vital membrane and cell functions modulated by phosphoinositides.

Animals↗

PubMed1994

Ontogenesis of quisqualate-associated phosphoinositide metabolism in various regions of the rat nervous system.

The effect of postnatal age on phosphoinositide metabolism per se and on quisqualate-stimulated phosphoinositide metabolism was characterized in synaptoneurosomes prepared from nine different regions of the rat nervous system, namely the brainstem, cerebellum, cerebral cortex, colliculi, hippocampus, hypothalamus, olfactory bulb, spinal cord and striatum. In the hippocampus, striatum, cerebellum, cerebral cortex, brainstem, colliculus and spinal cord, the basal levels of inositol phosphate (inositol-1-phosphate+inositol-4,5-bisphosphate) formation were maximal two days after birth and declined steeply to steady-state levels from the age of 10 postnatal days. Similarly, in the olfactory bulb, basal inositol phosphate synthesis did not significantly change when measured during the period from postnatal day 10 to 42. The extent of [3H]-inositol labelling of phosphoinositides as a function of age presented similar profiles when measured in hippocampal, striatal, cerebellar and cerebral cortical synaptoneurosomes, i.e. maximal at perinatal ages and minimal at adult ages. In the hypothalamus, [3H]-inositol labelling of phosphoinositides showed an increase from postnatal day 12 to higher levels from postnatal days 14 to 18 subsequently followed by a dramatic increase from postnatal day 21 to 42. A similar developmental trend was also obtained for basal inositol phosphate synthesis. On the whole, four types of developmental profiles for quisqualate-stimulated inositol phosphate formation (expressed as the percentage of the basal level and as the difference between stimulated and basal levels of radioactive inositol phosphates) were obtained depending on the nervous system region studied. In the early, prenatally developed nervous system regions, namely the brainstem and the spinal cord, no postnatal stimulation peaks of quisqualate-induced inositol phosphate formation were recorded. This was also the case for the colliculi when the stimulation of IP formation was expressed as the difference in basal and stimulated levels of inositol phosphates. Secondly, in the olfactory bulb a region known to possess a continuous capacity for developmental plasticity both structurally and functionally during the first three weeks of postnatal development, a simultaneous sustained high level of quisqualate stimulation of phosphoinositide metabolism (fluctuating around 200% of the basal level) during the early postnatal period was evident. Thirdly, in regions of the central nervous system like the cerebellum, cerebral cortex, hippocampus and the striatum known to undergo intense developmental activity during the first two postnatal weeks, peaks of quisqualate-stimulated phosphoinositide metabolism were initially detected around the first week after birth in each of these brain areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗