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PubMed1993

Contribution of G protein activation to fluoride stimulation of phosphoinositide hydrolysis in human neuroblastoma cells.

To examine the possibility that NaF enhances phosphoinositide-specific phospholipase C (PIC) activity in neural tissues by a mechanism independent of a guanine nucleotide binding protein (Gp), we have evaluated the contribution of Gp activation to NaF-stimulated phosphoinositide hydrolysis in human SK-N-SH neuroblastoma cells. Addition of NaF to intact cells resulted in an increase in the release of inositol phosphates (450% of control values; EC50 of approximately 8 mM). Inclusion of U-73122, an aminosteroid inhibitor of guanine nucleotide-regulated PIC activity in these cells, resulted in a dose-dependent inhibition of NaF-stimulated inositol lipid hydrolysis (IC50 of approximately 3.5 microM). When added to digitonin-permeabilized cells, NaF or guanosine-5'-O-thiotriphosphate (GTP gamma S) resulted in a three- and sevenfold enhancement, respectively, of inositol phosphate release. In the combined presence of optimal concentrations of NaF and GTP gamma S, inositol phosphate release was less than additive, indicative of a common site of action. Inclusion of 2-5 mM concentrations of guanosine-5'-O-(2-thiodiphosphate) (GDP beta S) fully blocked phosphoinositide hydrolysis elicited by GTP gamma S, whereas that induced by NaF was partially inhibited (65%). However, preincubation of the cells with GDP beta S resulted in a greater reduction in the ability of NaF to stimulate inositol phosphate release (87% inhibition). Both GTP gamma S and NaF-stimulated inositol phosphate release were inhibited by inclusion of 10 microM U-73122 (54-71%). The presence of either NaF or GTP gamma S also resulted in a marked lowering of the Ca2+ requirement for activation of PIC in permeabilized cells. These results indicate that in SK-N-SH cells, little evidence exists for direct stimulation of PIC by NaF and that the majority of inositol phosphate release that occurs in the presence of NaF can be attributed to activation of Gp.

Cell Membrane Permeability↗

PubMed1988

Noradrenaline stimulation of the phosphoinositide system: evidence for a novel hydrophobic inositol-containing compound in resistance arterioles.

1. Five inositol phosphates were extracted from adult rat resistance arterioles and separated by ion-exchange high performance liquid chromatography. 2. By use of this technique, inositol phosphates liberated were identified as inositol 1-phosphate, inositol 1,4-bisphosphate, inositol 1,3,4-trisphosphate, inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Stimulation of phosphoinositide hydrolysis with noradrenaline produced increases in inositol phosphate production. 3. Three inositol-containing phospholipids extracted from resistance arterioles were measured as their glycerol esters following deacylation, thereby permitting an analysis of both membrane and cytosolic components of the phosphoinositide signalling system. 4. A substantial agonist-sensitive pool of a previously undescribed inositol but not glycerol-containing lipid extract component was also identified in this tissue. 5. These experiments for the first time allow a precise description of phosphoinositide metabolism in resting and agonist-stimulated resistance arterioles and provide data on a novel compound possibly similar to that recently described in other tissues.

Animals↗

PubMed1990

Characterization of the muscarinic receptor subtype involved in phosphoinositide metabolism in bovine tracheal smooth muscle.

1. The muscarinic receptor subtype involved in the methacholine-induced enhancement of phosphoinositide metabolism in bovine tracheal smooth muscle was identified by using the M2-selective antagonist AF-DX 116 and the M3-selective antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methobromide, in addition to the M1-selective antagonist pirenzepine, in a classical Schild analysis. 2. All the antagonists shifted the methacholine dose-response curve to the right in a parallel and concentration-dependent fashion, yielding Schild plots with slopes not significantly different from unity. The pA2 values (6.94, 6.32 and 8.54 for pirenzepine, AF-DX 116 and 4-DAMP methobromide respectively) indicate that it is the M3 (smooth muscle/glandular), but not the M2 (cardiac) muscarinic receptor subtype, present in this tissue, that mediates phosphoinositide turnover, in accordance with our previous contractile studies. 3. The results provide additional evidence for the involvement of phosphoinositide turnover in the pharmacomechanical coupling between muscarinic receptor stimulation and contraction in (bovine tracheal) smooth muscle.

Animals↗

PubMed1995

Species-related differences in inotropic effects of angiotensin II in mammalian ventricular muscle: receptors, subtypes and phosphoinositide hydrolysis.

1. Experiments were carried out to clarify the mechanisms responsible for variations in the positive inotropic effect (PIE) of angiotensin II (AII) on ventricular muscles from various mammals. We examined the density of AII receptors, the relative proportions of receptor subtypes and the acceleration of the hydrolysis of phosphoinositide that was induced by AII, as well as the PIE of AII in ventricular muscles from the rabbit, dog, rat and ferret. 2. In the rabbit, AII (1 microM) in the presence of bupranolol (0.3 microM) and prazosin (0.1 microM) elicited a concentration-dependent PIE, which was antagonized by a selective AT1 subtype antagonist, losartan, but not by an AT2 antagonist, PD123319. AII did not have any inotropic effects in ventricular muscles from the dog, rat and ferret. 3. Specific high-affinity binding of [125I]-AII, with a similar Kd value in each case (1-2 nM), was observed with membrane fractions derived from ventricular muscle of all four species tested. 4. In the rabbit, losartan and PD123319 each displaced approximately 50% of [125I]-AII specific binding having high affinity for the receptors, and indicating that AT1 and AT2 subtypes were present in equal numbers. In the other species the AT1 subtype of receptors was predominant. 5. In all four species AII caused a concentration-dependent acceleration of the hydrolysis of phosphoinositide in ventricular slices that had been prelabelled with myo-[3H]-inositol. 6. The results indicate that the signal-transduction process distal to acceleration of the hydrolysis of phosphoinositide may be responsible for the wide range of species variations in the inotropic action of AII on mammalian ventricular myocardium.

Angiotensin I↗

PubMed1996

Coupling of metabotropic glutamate receptors to phosphoinositide mobilisation and inhibition of cyclic AMP generation in the guinea-pig cerebellum.

1. The effects of metabotropic glutamate receptor (mGluR) agonists on cyclic nucleotide and phosphoinositide turnover were investigated in adult guinea-pig cerebellar slices by use of radioactive precursors. 2.L-Glutamate, 1-aminocyclopentane-1S,3R-dicarboxylate (1S,3R-ACPD) and RS-3,5-dihydroxyphenylglycine (DHPG) evoked concentration-dependent increases in the accumulation of [3H]-inositol phosphates with pEC50 values of 2.98 +/- 0.02, 4.45 +/- 0.06 and 4.47 +/- 0.07, respectively. Maximal responses to these agents were 43 +/- 8, 52 +/- 12 and 84 +/- 11% of the response to 1 mM histamine, respectively. 3. The phosphoinositide response to 1S,3R-ACPD was antagonized in the presence of (+)-alpha-methyl-4-carboxyphenylglycine, with a calculated pKi value of 3.55 +/- 0.03. 4. Forskolin-stimulated accumulation of [3H]-cyclic AMP was not significantly altered in the presence of 10 microM DCG-IV or 300 microM 1S,3R-ACPD. Similarly, 300 microM 1S,3R-ACPD failed to alter isoprenaline-(1 microM) or 2-chloroadenosine (2-CA, 30 microM)-stimulated accumulation of [3H]-cyclic AMP. 5. Forskolin-stimulated accumulation of [3H]-cyclic AMP was concentration-dependently inhibited in the presence of L-glutamate and L-serine-O-phosphate (L-SOP) with pIC50 values of 2.91 +/- 0.17 and 2.86 +/- 0.04 with maximal inhibitions of 47 +/- 2 and 92 +/- 3%, respectively. L-2-Amino-4-phosphonobuty-rate (L-AP4) inhibited the forskolin response without saturating, evoking an inhibition of 71 +/- 7% at 3 mM. 6. 2-CA-evoked accumulation of [3H]-cyclic AMP was also inhibited by L-glutamate and L-SOP with pIC50 values of 2.71 +/- 0.03 and 2.72 +/- 0.08 and maximal inhibitions of 51 +/- 5 and 99 +/- 0%, respectively. L-AP4 inhibited the 2-CA response without saturating, evoking an inhibition of 68 +/- 1% at 3 mM. 7. Isoprenaline-evoked accumulation of [3H]-cyclic AMP was inhibited by L-glutamate and L-SOP with pIC50 values of 3.21 +/- 0.01 and 2.96 +/- 0.08 and maximal inhibitions of 88 +/- 2 and 93 +/- 3%, respectively. 8. These results suggest that the guinea-pig cerebellum expresses Group I and Group III mGluRs coupled to phosphoinositide turnover and inhibition of cyclic AMP generation, respectively.

2-Chloroadenosine↗

PubMed2006

Cooperation of phosphoinositides and BAR domain proteins in endosomal tubulation.

Phosphorylated derivatives of phosphatidylinositol (PtdIns) regulate many intracellular events, including vesicular trafficking and actin remodeling, by recruiting proteins to their sites of function. PtdIns(4,5)-bisphosphate [PI(4,5)P2] and related phosphoinositides are mainly synthesized by type I PtdIns-4-phosphate 5-kinases (PIP5Ks). We found that PIP5K induces endosomal tubules in COS-7 cells. ADP-ribosylation factor (ARF) 6 has been shown to act upstream of PIP5K and regulate endocytic transport and tubulation. ARF GAP with coiled-coil, ankyrin repeat, and pleckstrin homology domains 1 (ACAP1) has guanosine triphosphatase-activating protein (GAP) activity for ARF6. While there were few tubules induced by the expression of ACAP1 alone, numerous endosomal tubules were induced by coexpression of PIP5K and ACAP1. ACAP1 has a pleckstrin homology (PH) domain known to bind phosphoinositide and a Bin/amphiphysin/Rvs (BAR) domain that has been reported to detect membrane curvature. Truncated and point mutations in the ACAP1 BAR and PH domains revealed that both BAR and PH domains are required for tubulation. These results suggest that two ARF6 downstream molecules, PIP5K and ACAP1, function together in endosomal tubulation and that phosphoinositide levels may regulate endosomal dynamics.

ADP-Ribosylation Factor 6↗

PubMed2006

Phosphoinositide, phosphopeptide and pyridone interactions of the Abl SH2 domain.

Signaling proteins are localized and regulated by Src homology 2 domains which recognize phosphotyrosine-containing sequences. Recently, noncanonical ligands have been proposed for Src homology 2 domains including that of Abl and its breakpoint cluster region fusion, which causes chronic myelogenous leukemia. Here, the Abl Src homology 2 domain's binding sites and affinities for phosphotyrosine- and phosphoserine-containing motifs, phosphoinositides as well as a pyridone-based peptidomimetic inhibitor were determined using nuclear magnetic resonance spectroscopy in order to define their roles. The cognate Crk peptide ligand was bound with an affinity of 69 microM and, like the higher affinity peptidomimetic, engages the phosphotyrosine and +3 hydrophobic pockets while putative phosphoserine-containing breakpoint cluster region ligands are ruled out. Surprisingly, phosphatidylinositol 4, 5 bisphosphate interacts with an overlapping site through an electrostatic mechanism that does not appear to involve hydrophobic insertion into micelles. The conserved Arg36 residue in the FLVRES motif is required for both phosphotyrosine binding and for localization to phosphatidylinositol 4, 5 bisphosphate-containing liposomes, while Arg59 in the betaD strand is necessary for the phosphoinositide interaction. Thus the Src homology 2 domain of Abl, a myristoylated and membrane-localized protein, is able to interact directly with phosphoinositides through a multifunctional basic site that overlaps the phosphotyrosine pocket.

Animals↗

PubMed2001

Angiotensin AT(1) receptor phosphorylation and desensitization in a hepatic cell line. Roles of protein kinase c and phosphoinositide 3-kinase.

Desensitization and phosphorylation of the endogenous angiotensin II AT(1) receptor were studied in clone 9 liver cells. Agonist activation of AT(1) receptors blunted the response to subsequent addition of angiotensin II. Partial inhibition of the angiotensin II-induced calcium response was observed when cells were pretreated with dibutyryl cyclic AMP, tetradecanoyl phorbol acetate (TPA), vasopressin, or lysophosphatidic acid. All of these desensitization processes were associated with receptor phosphorylation. Angiotensin II-induced AT(1) receptor phosphorylation was partially blocked by the protein kinase C inhibitor bisindolylmaleimide I and by phosphoinositide 3-kinase inhibitors (wortmannin and LY294002); the actions of these inhibitors were not additive. Pertussis toxin pretreatment of cells also partially inhibited angiotensin II-induced AT(1) receptor phosphorylation. TPA-induced AT(1) receptor phosphorylation was completely blocked by bisindolylmaleimide I. AT(1) receptor phosphorylation was also induced by vasopressin and lysophosphatidic acid, and these effects were partially inhibited by bisindolylmaleimide I. Angiotensin II increased Akt/PKB (protein kinase B) phosphorylation and protein kinase C membrane association. The effect on Akt/PKB phosphorylation was blocked by phosphoinositide 3-kinase inhibitors. These findings indicate that clone 9 cells exhibit both homologous and heterologous desensitization in association with AT(1) receptor phosphorylation. In these hepatic cells, angiotensin II-induced receptor phosphorylation involves pertussis toxin-sensitive and -insensitive G proteins, and is mediated in part through protein kinase C and phosphoinositide 3-kinase.

Angiotensin II↗

PubMed1988

Lithium blocks a phosphoinositide-mediated cholinergic response in hippocampal slices.

The effects of lithium on inositol phosphate metabolism may account for the therapeutic actions of lithium in affective disorder. Muscarinic stimulation of the phosphoinositide system blocks synaptic inhibitory actions of adenosine in the hippocampal slice. At therapeutic concentrations, lithium diminished this muscarinic response, whereas rubidium, which does not affect phosphoinositide metabolism, had no effect. A dampening of phosphoinositide-mediated neurotransmission may explain the normalizing effects of lithium in treating both mania and depression.

Adenosine↗

PubMed1986

The metabolism of phosphoinositide-derived messenger molecules.

The phosphoinositides are minor phospholipids present in all eukaryotic cells. They are storage forms for messenger molecules that transmit signals across the cell membrane and evoke responses to extracellular agonists. The phosphoinositides break down to liberate messenger molecules or precursors of messenger molecules. Many different compounds are formed, although the functions of only a few are understood. Recent studies elaborating the pathways for formation of products from phosphoinositides and the factors controlling their metabolism are summarized here.

Arachidonic Acid↗

PubMed2002

Visualizing cellular phosphoinositide pools with GFP-fused protein-modules.

Inositol phospholipids are well known for their pivotal role in calcium signaling as precursors of important second messengers generated in response to various stimuli. However, over the last 10 years, inositides have also emerged as universal signaling components present in virtually every membrane of eukaryotic cells. These lipids are locally produced and degraded by the numerous inositide kinase and phosphatase enzymes, to control the recruitment and activity of protein signaling complexes in specific membrane compartments. The spatial and temporal constraints imposed on changes in cellular inositides pose new challenges in finding experimental techniques through which such changes can be examined. Taking advantage of the protein domains selected by evolution to recognize cellular phosphoinositides, we have created fluorescent molecules by fusing these domains to the improved version of green fluorescent protein (EGFP); the distribution of these fusion proteins can be followed within live cells, thereby reporting on changes in phosphoinositides. Although this technique is one of the few that provide information on phosphoinositide dynamics in live cells with subcellular resolution and has rapidly gained popularity, it also has limitations that need to be taken into account when interpreting the data. Here, we summarize our experience in designing and using these constructs and review our position concerning the interpretation of the data obtained by this technique.

Animals↗

PubMed1990

Stimulatory effect of staphylococcal leukocidin on phosphoinositide metabolism in rabbit polymorphonuclear leukocytes.

When rabbit polymorphonuclear leukocytes (PMNs) were incubated with staphylococcal leukocidin (F and S components) in the presence of 32Pi at 37 degrees C, incorporation of 32Pi into phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2) occurred after a lag phase of 10 s and reached a maximal level at 60 s of 50- and 30-fold increase, respectively, compared with that of the control in the absence of the toxin. Whereas the amount of 32P radioactivity incorporated in PIP and PIP2 decreased to control levels in a few minutes, 32P incorporation into phosphatidic acid (PA) continuously increased over 3 min. These findings suggested an early activation of phosphoinositide-specific phospholipase C in rabbit PMNs by leukocidin as shown by the rapid breakdown of PIP and PIP2 accompanied by the appearance of PA. The stimulatory effect of leukocidin on some enzymatic activities of the phosphatidylinositol pathway was further investigated by using PMN cell membrane preparations. In the presence of both the F and S components, enhanced 32P incorporation was observed not only in PIP2 and PA but also in PIP. While the F component mainly enhanced 32P incorporation into PIP2 and PA, the S component alone had no effect on 32P incorporation into PIP, PIP2, and PA. The F component alone enhanced conversion of PIP to [32P]PIP2 in the presence of unlabeled PIP and [gamma-32P]ATP, through the activation of PIP kinase. PIP kinase activity was potentiated by the addition of NAD and GTP. Subsequent formation of [32P]PA was also enhanced by the F component, resulting from activation of the phosphoinositide-specific phospholipase C. These results suggested that the F component of staphylococcal leukocidin is responsible for the enhancement of phosphoinositide metabolism in rabbit PMN cell membranes.

Animals↗

PubMed2006

Phosphoinositides are involved in control of the glucose-dependent growth resumption that follows the transition phase in Streptomyces lividans.

The interruption of the sblA gene of Streptomyces lividans was previously shown to lead to relief of glucose repression of the normally strongly glucose-repressed alpha-amylase gene. In addition to this relief, an early entry into stationary phase was observed when cells were grown in a minimal medium containing glucose as the main carbon source. In this study, we established that this mutant does not resume growth after the transition phase when cultured in the complex glucose-rich liquid medium R2YE and sporulates much earlier than the wild-type strain when plated on solid R2YE. These phenotypic differences, which were abolished when glucose was omitted from the R2YE medium, correlated with a reduced glucose uptake ability of the sblA mutant strain. sblA was shown to encode a bifunctional enzyme possessing phospholipase C-like and phosphoinositide phosphatase activities. The cleavage of phosphoinositides by SblA seems necessary to trigger the glucose-dependent renewed growth that follows the transition phase. The transient expression of sblA that takes place just before the transition phase is consistent with a regulatory role for this gene during the late stages of growth. The tight temporal control of sblA expression was shown to depend on two operator sites. One, located just upstream of the -35 promoter region, likely constitutes a repressor binding site. The other, located 170 bp downstream of the GTG sblA translational start codon, may be involved in the regulation of the degradation of the sblA transcript. This study suggests that phosphoinositides constitute important regulatory molecules in Streptomyces, as they do in eukaryotes.

Bacterial Proteins↗

PubMed2006

Spatial localization of m-calpain to the plasma membrane by phosphoinositide biphosphate binding during epidermal growth factor receptor-mediated activation.

Calpain activity is required for de-adhesion of the cell body and rear to enable productive locomotion of adherent cells during wound repair and tumor invasion. Growth factors activate m-calpain (calpain 2, CAPN2) via ERK/mitogen-activated protein kinases, but only when these kinases are localized to the plasma membrane. We thus hypothesized that m-calpain is activated by epidermal growth factor (EGF) only when it is juxtaposed to the plasma membrane secondary to specific docking. Osmotic disruption of NR6 fibroblasts expressing the EGF receptor demonstrated m-calpain being complexed with the substratum-adherent membrane with this increasing in an EGF-dependent manner. m-Calpain colocalized with phosphoinositide biphosphate (PIP(2)) with exogenous phospholipase C removal of phosphoinositides, specifically, PI(4,5)P(2) but not PI(4)P(1) or PIP(3), releasing the bound m-calpain. Downregulation of phosphoinositide production by 1-butanol resulted in diminished PIP(2) in the plasma membrane and eliminated EGF-induced calpain activation. This PIP(2)-binding capacity resided in domain III of calpain, which presents a putative C2-like domain. This active conformation of this domain appears to be partially masked in the holoenzyme as both activation of m-calpain by phosphorylation at serine 50 and expression of constitutively active phosphorylation mimic glutamic acid-increased m-calpain binding to the membrane, consistent with blockade of this cascade diminishing membrane association. Importantly, we found that m-calpain was enriched toward the rear of locomoting cells, which was more pronounced in the plasma membrane footprints; EGF further enhanced this enrichment, in line with earlier reports of loss of PIP(2) in lamellipodia of motile cells. These data support a model of m-calpain binding to PIP(2) concurrent with and likely to enable ERK activation and provides a mechanism by which cell de-adhesion is directed to the cell body and tail as phospholipase C-gamma hydrolyzes PIP(2) in the protruding lamellipodia.

Animals↗

PubMed2004

Control of cyclin G2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead.

Cyclin G2 is an unconventional cyclin highly expressed in postmitotic cells. Unlike classical cyclins that promote cell cycle progression, cyclin G2 blocks cell cycle entry. Here we studied the mechanisms that regulate cyclin G2 mRNA expression during the cell cycle. Analysis of synchronized NIH 3T3 cell cultures showed elevated cyclin G2 mRNA expression levels at G(0), with a considerable reduction as cells enter cell cycle. Downregulation of cyclin G2 mRNA levels requires activation of phosphoinositide 3-kinase, suggesting that this enzyme controls cyclin G2 mRNA expression. Because the phosphoinositide 3-kinase pathway inhibits the FoxO family of forkhead transcription factors, we examined the involvement of these factors in the regulation of cyclin G2 expression. We show that active forms of the forkhead transcription factor FoxO3a (FKHRL1) increase cyclin G2 mRNA levels. Cyclin G2 has forkhead consensus motifs in its promoter, which are transactivated by constitutive active FoxO3a forms. Finally, interference with forkhead-mediated transcription by overexpression of an inactive form decreases cyclin G2 mRNA expression levels. These results show that FoxO genes regulate cyclin G2 expression, illustrating a new role for phosphoinositide 3-kinase and FoxO transcription factors in the control of cell cycle entry.

Animals↗

PubMed2000

The effect of endurance training on phosphoinositide metabolism of extensor digitorum longus in rat.

We tested the hypothesis that endurance training results in changes in inositol triphosphate (InsP3) production from membrane phosphoinositides in trained muscles during contractile activity, which might have implications for fatigue involving calcium-release mechanisms. The extensor digitorum longus (EDL) muscles of endurance-trained rats were measured for membrane phosphoinositides, fatigability, and the production of inositol phosphates resulting from a 10-s tetanic contraction in vitro. In the latter, training resulted in a 22% increase in the production of inositol phosphates, in spite of lower phosphoinositides per muscle. In a separate group of animals, pretreatment of EDL in vitro for 15 min with 20 mM lithium resulted in a gradual decrease in tetanic forces at 100 Hz and increased fatigability. These results show for the first time that this metabolic system adapts to increased use and may contribute to the associated increased fatigue resistance, through its modulation of calcium release by sarcoplasmic reticulum.

Analysis of Variance↗

PubMed1995

Fetal bovine serum induces changes in fatty acid composition of Trypanosoma cruzi phosphoinositides.

Fetal bovine serum (FBS) is a necessary constituent of the culture media employed to foster the growth of Trypanosoma cruzi epimastigote forms. In different laboratories, the serum is used at final concentrations of 5 or 10%. We have normally supplemented the complex medium with 10% FBS. Under this condition we have described the fatty acid composition of the total lipids and of the phosphoinositide fractions. Additionally, we have reported the increase of polyphosphoinositides and phosphatidic acid after cholinergic stimulation. Since further attempts to reproduce these results with 5% FBS in the culture medium were not successful, the effect of the FBS concentration on the fatty acid composition of phospholipids from the T. cruzi epimastigote forms was thoroughly examined. This work showed that when the FBS concentration supplementing the culture medium was reduced from 10 to 5%, the fatty acid composition of the phosphoinositides was altered while the other major phospholipids were not significantly affected. The most relevant result was the decrease in the content of linoleic acid (18:2) and the increase of palmitoleic acid (16:1) in phosphatidylinositol 4,5-bisphosphate. Phosphatidylinositol (PI) and phosphatidylinositol phosphate also exhibited similar changes in the same fatty acids. The C2 fatty acid composition of the phosphoinositides, under the same conditions, is also reported here for the first time.

Animals↗

PubMed1991

Enhanced arterial contractility to noradrenaline in diabetic rats is associated with increased phosphoinositide metabolism.

The purpose of this study was to investigate whether the increased contractile responsiveness of aortae from male rats with 12-14 week streptozotocin-induced diabetes to noradrenaline is associated with alterations in phosphoinositide metabolism. The contractile response to noradrenaline (10 microM) in both the presence and absence of extracellular calcium was significantly enhanced in aortae from diabetic rats. No significant differences were found between control and diabetic arteries in the basal incorporation of 32P and [3H]myo-inositol into phosphoinositides, or in the basal accumulation of [32P]phosphatidic acid and [3H]inositol phosphates. However, noradrenaline (10 microM) caused significantly greater breakdown of [32P]phosphatidylinositol 4,5-bisphosphate and formation of [32P]phosphatidic acid and [3H]inositol phosphates in diabetic aortae than in control preparations. The production of [3H]inositol phosphates induced by noradrenaline was selectively reduced by the alpha 1-adrenoceptor antagonist, prazosin, in both control and diabetic tissues. These results indicate that phosphoinositide metabolism in response to noradrenaline via stimulation of alpha 1-adrenoceptors is enhanced in aortae from chronic streptozotocin-diabetic rats. The increase in inositol 1,4,5-trisphosphate and 1,2-diacylglycerol production that presumably results could be responsible, at least in part, for the enhanced contractile response of aortae from diabetic rats to noradrenaline.

Animals↗