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PubMed1991

Age-dependent changes in receptor-stimulated phosphoinositide turnover in the rat hippocampus.

To study the changes in the hippocampal cholinergic system of chronologically old and behaviorally impaired animals, old (21 months of age) and young (3 months of age) male, Fischer-344 rats were used. The aged animals were tested on a reference memory task (Morris water maze) and found to be functionally impaired as compared to the young controls. Carbachol-stimulated phosphoinositide metabolism was measured in hippocampal slices from young and old rats. Slices were prelabeled with 3H-inositol for 120 min and subjected to muscarinic stimulation in the presence of lithium. Following extraction of the slices with acidified solvent mixture, the inositolphosphates present in the aqueous fraction were isolated by ion exchange chromatography. Receptor-stimulated release of inositolphosphates (IPs) was found to be increased in the hippocampus of older animals. This age-related enhancement of IP release was in contrast to the decrease in choline acetyltransferase (CHAT) activity in the hippocampus. We postulate that alterations in the G-protein coupling with the muscarinic receptor leads to an increase in the phosphoinositide turnover in part as a compensatory mechanism for neuronal cell death and reduced transmitter levels.

Aging↗

PubMed1993

Effect of repeated organophosphate administration on carbachol-stimulated phosphoinositide hydrolysis in the rat brain.

The effects of repeated exposure to two organophosphates on the turnover of phosphoinositides, the second messenger system coupled to the M1 and M3 subtypes of muscarinic receptors, were examined in the rat hippocampus. Repeated diisopropylfluorophosphate (DFP) exposure (0.2-0.8 mg/kg, SC) decreased brain acetylcholinesterase activity and muscarinic receptor density. The incorporation of [3H]myoinositol into brain slices was also decreased. Phosphoinositide turnover was measured as the accumulation of [3H]inositol phosphates (IP) in the presence of lithium. DFP did not affect basal IP accumulation, but decreased carbachol-stimulated IP accumulation in the hippocampus after 0.4 and 0.8 mg/kg. The effects of repeated disulfoton administration (2.0 mg/kg, IP) were also examined in the hippocampus. Similar to DFP, repeated disulfoton exposure decreased acetylcholinesterase activity, receptor density, and carbachol-stimulated IP accumulation. The incorporation of myoinositol, however, was increased in disulfoton-treated rats. These data indicate that repeated organophosphate exposure results in a functional decrease in muscarinic receptor activity, as well as changes in myoinositol incorporation into phospholipids.

Animals↗

PubMed1994

Differences in ligand binding and phosphoinositide turnover between M1 muscarinic receptor gene transfected cells and mouse and rat brain membranes.

The present study describes some unexpected receptor mediated effects of N-methylcarbamylcholine on mouse M1 muscarinic receptor gene transfected cell line (M1Y1) that were not evident from biochemical studies with mouse and rat brain tissue where N-methylcarbamylcholine exhibited only nicotinic properties. Although N-methylcarbamycholine was devoid of muscarinic properties in mouse and rat brain preparations, as determined by phosphoinositide turnover and inhibition of [3H]QNB binding, it exhibited significant muscarinic characteristics in the transfected M1Y1 cell line. At a concentration of 10(-6) M or greater, N-methylcarbamycholine caused a transient increase in intracellular Ca2+ of 50 s duration that was reversible by atropine or pirezepine. The Ca(2+)-transient was not elicited by other nicotinic agents such as nicotine and N,N-dimethylcarbamylcholine, a close analogue of N-methylcarbamylcholine, with comparable affinity for nicotinic receptors and devoid of muscarinic activity. N-Methylcarbamylcholine also stimulated phosphoinositide turnover in M1Y1 cells with an estimated EC50 value 10 times greater than that of carbachol, and the effect was blocked by atropine. Both carbachol and N-methylcarbamycholine inhibited [3H]QNB binding in a concentration-dependent manner; however, the IC50 for carbachol was over two orders of magnitude greater than that observed in mouse and rat brain membranes. In considering possible explanations for the differential characteristics of N-methylcarbamylcholine in mouse and rat brain as compared to the transfected M1Y1 cells, it was concluded that the difference may be attributable to differences in the receptor-transduction coupling efficiency and the microenvironment of the muscarinic receptors.

Adrenal Glands↗

PubMed1989

Mammalian phosphoinositide-specific phospholipase C isoenzymes.

Procaryotic and eucaryotic cells have evolved multiple pathways for communication with their external environment. The inositol 1,4,5-trisphosphate/diacylglycerol second messenger system is an example of such a signal transduction pathway which is present in multicellular eucaryotic organisms. Binding of an agonist to a specific cell surface receptor promotes rapid hydrolysis of phosphatidylinositol 4,5-bisphosphate. The pivotal enzyme for this second messenger system is phosphoinositide-specific phospholipase C which hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate the two second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. Recently, much progress has been made in the purification, characterization and cDNA cloning of multiple PI-PLC isoenzymes. The results of the recent studies on phosphoinositide-specific phospholipase C are reviewed.

Amino Acid Sequence↗

PubMed1994

Activation of phosphoinositide metabolism by parathyroid hormone in growth plate chondrocytes.

Parathyroid hormone (PTH) is one of the most potent stimulators of growth plate chondrocyte mitogenesis that has been reported. However, study of the second messenger signaling mechanisms involved in the transduction of the hormone's effects on these cells is incomplete. Our data indicate that in addition to stimulating cyclic adenosine-3'5'-monophosphate metabolism, PTH also activates the phosphoinositide cascade, the pathway responsible for the generation of inositol-1,4,5-trisphosphate dependent Ca2+ signals. Our conclusion that PTH activates the phosphoinositide cascade is based on data that demonstrate: (1) the Ca2+ transients evoked by the hormone are dependent on intracellular Ca2+ stores; (2) the hormone stimulates the release of radiolabeled inositol from GPC plasma membranes; and (3) the hormone stimulates a greater than 8-fold increase in cytosolic inositol-1,4,5-trisphosphate pool size.

Animals↗

PubMedDate not supplied

Phosphoinositide metabolism in airway smooth muscle.

Agonist-stimulated hydrolysis of phosphatidylinositol 4,5-bisphosphate, which generates inositol 1,4,5-trisphosphate and sn-1,2-diacylglycerol, is thought to be one of the major mechanisms underlying pharmacomechanical coupling in airway smooth muscle. This article is a review of the currently available information on phosphoinositide and inositol 1,4,5-trisphosphate metabolism in this tissue and includes data on inositol 1,4,5-trisphosphate-induced Ca2+ release and the receptor mediating this effect. The final section outlines the potential mechanisms underlying physiological regulation of phosphoinositide metabolism by other second-messenger pathways operative in this tissue.

Animals↗

PubMed1986

Phosphoinositides provide a regulatory mechanism of surface charge and active transport.

Yeast cells, when grown in the presence of arsenate, are capable of accumulating phosphoinositides (PI) at the expense of inhibiting their degradation more than their synthesis. PI levels return to normal when the cells are cultured or exposed to media without arsenate. These reversible changes are employed as a tool to test the effect of inositide accumulation and dynamics on several membrane properties. In the PI-rich cells, phosphate and arsenate transport from low external concentrations (high affinity systems), as well as the transport of glycine, which enter the cells accompanied by protons, were increased. The proton ejection energized by glucose is also enhanced in the PI-rich cells that show a more efficient potassium inflow at pH 4.0-4.5. The membrane surface potential of the PI-rich cells was found to be 2-times higher than that of the normal cells, in agreement with the 2-fold increment in the PI. All the above mentioned alterations in membrane properties are reverted when the PI content of the PI-rich cells is reduced to the level of normal cells. The results show the participation of the phosphoinositides in the formation, maintenance and regulation of the membrane surface potential and their possible influence upon transport mechanisms.

Arsenates↗

PubMed1995

Prazosin reduces myocardial ischemia/reperfusion-induced Ca2+ overloading in rat heart by inhibiting phosphoinositide signaling.

The aim of this study was to establish whether or not alpha 1-adrenergic receptors are implicated in triggering phosphoinositide hydrolysis and intracellular Ca2+ accumulation during myocardial ischemia and reperfusion. In isolated perfused rat hearts, the selective alpha 1-receptor antagonist prazosin abolished the increase in radioactivity incorporation into cellular inositol phosphates induced by 30 min ischemia followed by 30 min reperfusion, and selectively blocked the degradation of phosphoinositides; only minor changes in the ischemia/reperfusion-induced loss of other classes of phospholipids were seen. In addition, a prazosin-induced decrease of ischemia/reperfusion Ca2+ overloading was documented in real-time recordings of epicardial cytosolic free Ca2+ in fura 2-loaded hearts. An inhibition of early ischemic Ca2+ rise was observed, as well as a lower peak of cytosolic free Ca2+ and a more rapid reversal to normal values during reperfusion. Moreover, alpha 1-adrenergic blockade resulted in a significant improvement in the recovery of myocardial function during reperfusion: an increased left ventricular developed pressure and maximum rate of rise of systolic pressure paralleled the decrease in time-averaged cytosolic Ca2+ and the increase in amplitude of Ca2+ transients, respectively. It is concluded that myocardial Ca2+ overloading during ischemia and reperfusion may be triggered by alpha 1-adrenergic receptor-induced polyphosphoinositide hydrolysis.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1992

Thyrotropin releasing hormone (TRH) and a degradation stabilized analogue (RX77368) stimulate phosphoinositide turnover in cultured astrocytes in a regionally specific manner.

Whilst the CNS effects of thyrotropin releasing hormone (TRH) may result from a direct action on neurones it is also a possibility that another cell type may mediate an indirect action. A potential candidate for such a role is the astrocyte. The ability of TRH and a stable analogue RX77368 (di-methyl proline TRH) to stimulate phosphoinositide turnover has been investigated in cultured astrocytes from a number of CNS regions. Significant increases in turnover were noted in three of the four regions studied. Percentage values were: in spinal cord, 33% TRH, 31% RX77368 (n = 15); in brain stem, 33% TRH, 37% RX77368 (n = 6); in cerebellum, 72% TRH, 73% RX77368 (n = 6); in cortex, 4% TRH, 13% RX77368 (n = 6). EC50 values for both peptides were in the picomolar range. These results indicate that some astrocytes in vitro possess functional TRH receptors linked to the phosphoinositide second messenger system and hence this cell type would potentially be capable of mediating an indirect action of the peptide. Also, because the response was limited to certain regions, heterogeneity in receptor expression is implied. Furthermore, in the light of other evidence to support astrocyte heterogeneity within a region, we suggest that certain characteristics of the response seen in our experiments may be the result of TRH receptors being restricted to a subpopulation of astrocytes within a given culture. Thus, our data show that astrocytes prepared from some CNS regions possess functionally coupled TRH receptors.

Animals↗

PubMed1986

Arachidonic acid inhibition of insulin action and phosphoinositide turnover in fat cells.

Incubation of isolated rat adipocytes with 1 microM arachidonic acid (20:4) coupled to equimolar amounts of bovine serum albumin (BSA) results in the cellular uptake of the fatty acid and a subsequent inhibition of insulin-stimulated antilipolysis and lipogenesis without altering glucose transport. These effects are apparently not mediated at the insulin receptor level since insulin binding is not altered in arachidonate-enriched fat cells. In addition, effects on antilipolytic and lipogenic are not specific for arachidonic acid. Oleic or palmitic acid can mimic these effects in both insulin-stimulated and PGE2-stimulated cells. Adipocyte enrichment with 20:4, however, specifically inhibits the insulin-stimulated turnover of phosphoinositides. The latter can be specifically prevented by preincubation with ibuprofen. These results suggest that the level of intracellular arachidonate may play a major role in modulating insulin-stimulated phosphoinositide turnover and thereby indirectly regulate certain aspects of insulin action which involve lipid metabolism.

Adipose Tissue↗

PubMed1990

Influence of stress on phosphoinositides in rat brain.

The effect of a single 1 h immobilization or repeated 1 h immobilization for 10 days on the levels of phosphoinositides in rat whole brain was investigated. Immediately after 1 h immobilization the levels of phosphatidylinositol (PI) and phosphatidylinositol 4,5-bisphosphate (PIP2) were decreased by 22 and 31%, respectively, but phosphatidylinositol 4-phosphate (PIP) was not significantly reduced. These changes were restored to normal levels 20 h after the immobilization. After repeated daily immobilizations the effect of stress on phosphoinositides was no longer observed. These results show that acute stress perturbs the concentration of PIP2 (precursor of second messengers) and indicate adaptation to acute stress in animals subjected to repeated stress.

Animals↗

PubMed1990

Selective activation of phosphoinositide hydrolysis by a rigid analogue of glutamate.

Ibotenate and trans-D,L-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) are rigid analogues of glutamate. Ibotenate has been shown to activate phosphoinositide hydrolysis in rat brain slices. We now report that trans-ACPD also stimulates phosphoinositide hydrolysis but with much higher potency and efficacy than ibotenate. The pharmacological profiles, regional distributions, and developmental regulation of the responses to ibotenate and trans-ACPD are similar, suggesting that these agonists act at the same site. However, trans-ACPD is the first agonist described that is selective for this receptor relative to other excitatory amino acid receptor subtypes.

Amino Acids↗

PubMed1990

Further characterisation of excitatory amino acid receptors coupled to phosphoinositide metabolism in astrocytes.

Excitatory amino acids stimulate phosphoinositide breakdown in astrocytes with the following rank order of effect: quisqualate greater than ibotenate = glutamate greater than kainate greater than N-methyl-D-aspartate. Quisqualate-induced responses were resistant to blockade with a range of receptor antagonists whereas those to glutamate were partially reversed by gamma-D-glutamylaminosulphonic acid and gamma-D-glutamylglycine. These antagonists were, however, more effective against kainate-stimulated phosphoinositide metabolism. These experiments together with those where combinations of agonists were used, suggest that the kainate-induced and, to some extent, the glutamate-induced responses were due to membrane depolarisation and that quisqualate activates a non-ionotropic class of receptor at which glutamate and ibotenate are partial agonists.

Astrocytes↗

PubMed1990

A novel role for dopamine: inhibition of muscarinic cholinergic-stimulated phosphoinositide hydrolysis in rat brain cortical membranes.

Dopamine inhibited phosphoinositide breakdown as stimulated by carbachol in rat brain cortical membranes. The IC50 value was 14 +/- 2 microM for dopamine's inhibition of phosphatidylinositol hydrolysis as stimulated by 1 mM carbachol. The inhibition was found at low (0.1 microM), but not high (greater than 0.3 microM), concentrations of the non-hydrolyzable guanine nucleotide analog, GTP gamma S. Pharmacological characterization of the response indicated that the dopamine effects were mediated by D1 receptors. The assay conditions precluded any involvement of cyclic-AMP as a mediator of the dopamine response, and thus, a novel role is proposed for dopamine in cortex working through D1 receptors to inhibit phosphoinositide degradation.

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

PubMed1991

Pertussis toxin-sensitive G-protein mediates galanin's inhibition of scopolamine-evoked acetylcholine release in vivo and carbachol-stimulated phosphoinositide turnover in rat ventral hippocampus.

The effects of intracerebroventricular (i.c.v.) injections of pertussis toxin were investigated on the inhibitory action of galanin on acetylcholine release and phosphoinositide breakdown stimulated by muscarinic agents in rat ventral hippocampus. Pertussis toxin (0.6 micrograms, i.c.v., 96 h) counteracted the in vitro inhibitory effect of galanin (3.1 nmol) on phosphoinositide breakdown stimulated by carbachol without altering the stimulatory action of the cholinergic agonist on signal transduction, in miniprisms from rat ventral hippocampus. Pertussis toxin also abolished the in vivo effect of galanin on scopolamine-stimulated acetylcholine release in vivo but did not affect basal acetylcholine release. The results indicate that pertussis toxin-sensitive G-protein(s) mediates the galanin receptor regulation of pre- and postsynaptic cholinergic functions in the ventral hippocampus.

Acetylcholine↗

PubMed1991

Chronic haloperidol treatment attenuates receptor-mediated phosphoinositide turnover in rat brain slices.

The long-term effects of haloperidol on phosphoinositide turnover in rat brain slices were investigated. Continuous treatment with haloperidol decanoate (21 mg/kg I.M. biweekly for 6 weeks) significantly attenuated carbachol- and norepinephrine (NE)-induced inositol phosphate accumulation in rat frontal cortex and hippocampus. In the striatum, the haloperidol treatment also significantly decreased carbachol-stimulated inositol phosphate level but did not significantly affect NE-sensitive phosphoinositide turnover. These effects were not observed in rats treated with a single dose of haloperidol (1.5 mg/kg). Basel levels of inositol phosphate in these 3 brain regions did not change following continuous or single haloperidol doses.

Animals↗

PubMed1992

A neurophysiological study of a lithium-sensitive phosphoinositide system in the hamster suprachiasmatic (SCN) biological clock in vitro.

Lithium lengthens the period of free-running circadian rhythms in many species. In mammals the hypothalamic suprachiasmatic nucleus (SCN) has been identified as a biological clock which generates circadian rhythms. The effect of lithium-induced depletion of the intracellular pool of inositol, leading to decreased intracellular second messengers IP3 and DAG, was examined neurophysiologically. Extracellular recordings were obtained from spontaneously discharging SCN neurones maintained in vitro. Superfusion of slices with lithium-containing (0.1-30 mM) aCSF, but not rubidium-containing aCSF, suppressed neuronal firing in a dose-dependent manner. Lithium-induced suppressed firing was reversed by myo-inositol, but not by epi-inositol. These studies provide evidence for basal phosphoinositide turnover in neurones and implicate a lithium-sensitive phosphoinositide system in the maintenance of the spontaneous discharge activity of SCN neurones.

Animals↗

PubMed1993

Reduction of phosphoinositide hydrolysis by L-amino-3-phosphonopropionate may be caused by the inhibition of synthesis of phosphatidylinositols.

L-Amino-3-phosphonopropionate (L-AP3), a putative antagonist of metabotropic glutamate receptors, inhibited the formation of [3H]inositol phosphates induced by (1S,3R)1-aminocyclopentane-1,3-dicarboxylic acid in rat hippocampal slices. The inhibition was accompanied by a decrease in the levels of [3H]phosphatidylinositols ([3H]PIs). Preincubation of slices with L-AP3 inhibited the incorporation of [3H]myo-inositol into PI fractions. The effects of L-AP3 was in contrast with those of a typical receptor antagonist, atropine; atropine inhibited carbachol-induced phosphoinositide hydrolysis, but the levels of [3H]PIs were not affected. These findings suggest that the inhibition of phosphoinositide hydrolysis by L-AP3 is not due to the receptor antagonism but may be caused by the inhibition of synthesis of PIs.

Alanine↗