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At least 433 records · Page 24Linked to original sources
PubMed1993

Incorporation of [3H]inositol into phosphoinositides and inositol phosphates by rabbit blastocysts.

Preimplantation rabbit embryos collected at the early morula stage were cultured to blastocysts in the presence of [3H]inositol. The blastocysts were lysed, and both the aqueous and lipid portions were analysed for incorporated radioactivity. Thin-layer chromatographic separation of the lipid portion indicated that [3H]inositol was incorporated into phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate. HPLC anion-exchange chromatography indicated that [3H]inositol was incorporated into inositol phosphates, including the two second messengers, inositol 1,4,5-triphosphate and inositol 1,3,4,5-tetrakisphosphate, and also inositol monophosphate and inositol 1,4-bisphosphate. These results provide evidence that rabbit blastocysts may have an active phosphatidylinositol second messenger system, which may be responsive to intrauterine factors or intraembryonic paracrine factors.

Animals↗
PubMed1999

Clinical subtyping reveals significant differences in calcium-dependent phospholipase A2 activity in schizophrenia.

BACKGROUND: Inconsistent results in the study of phospholipid metabolism in schizophrenia may reflect the heterogeneous nature of the illness(es). Differences in patients' responses to niacin, a compound causing vasodilation via stimulation of phospholipid dependent signaling cascades, defines more homogeneous patient subgroups in which the rate limiting enzyme of this signaling pathway, phospholipase A2 (PLA2), can be studied. METHODS: Subjects were categorized as niacin-insensitive (10 schizophrenic patients and 1 control) or niacin-sensitive (13 schizophrenic patients and 29 controls). Comparisons of serum calcium-dependent PLA2 were undertaken with and without consideration of niacin sensitivity. RESULTS: Significantly more schizophrenic patients were niacin-insensitive than controls (chi 2 (1) = 12.8, p < .001). Comparison of mean serum calcium-dependent PLA2 level of all schizophrenic subjects with all healthy controls revealed no statistical difference (t(51) = .79, NS). Subtyping the schizophrenia group by niacin sensitivity/insensitivity, however, allowed significant differences to emerge (F(2,49) = 4.40, p = .018). Post-hoc tests showed the mean PLA2 activity level of niacin-sensitive subjects was lower than that of healthy subjects. CONCLUSIONS: Treatment strategies which increase calcium-dependent PLA2 activity may aid in reducing states of excess dopaminergic activity by activating second messenger systems rather than receptor blockade.

Adult↗
PubMed1999

Regulation of chick dorsal root ganglion growth cone filopodia by protein kinase C.

Growth cone filopodia function both as structural and sensory devices during neuronal pathfinding and their presence is important for correct growth cone navigation. It is assumed that a growth cone can adjust the area of the environment it can explore by regulating the length and number of its filopodial sensors, and in several cell types, these parameters are controlled by the intracellular calcium concentration ([Ca(2+)](i)). In the present report, we address the question whether [Ca(2+)](i) is a general regulator of growth cone filopodia, or whether different cell types utilize different second-messenger systems for this purpose. We show that increasing [Ca(2+)](i) in growth cones of chick dorsal root ganglion (DRG) neurons does not affect average filopodial length in this cell type, suggesting that this parameter is not controlled by [Ca(2+)](i) in chick DRG neurons. Further, we demonstrate that the second-messenger protein kinase C (PKC) is involved in the regulation of filopodial length in chick DRG neurons. Activation of PKC with the phorbol ester, phorbol myristate-13-acetate (PMA), caused filopodial shortening, whereas inhibition of PKC with either bisindolylmaleimide I or calphostin C caused a significant elongation of filopodia. Although the pathway through which PKC mediates its effect on growth cone filopodia in chick DRG neurons remains to be identified, our results indicate that filopodial regulation by [Ca(2+)](i), though clearly important in several other neuronal cell types in vitro, appears to be less important in chick DRG neurons. Rather, we find that in chick DRG neurons, filopodial parameters are controlled by PKC.

Animals↗
PubMed1998

Glutathione depletion exacerbates impairment by oxidative stress of phosphoinositide hydrolysis, AP-1, and NF-kappaB activation by cholinergic stimulation.

Oxidative stress appears to contribute to neuronal dysfunction associated with Alzheimer's disease and other CNS neurodegenerative disorders. This investigation examined if oxidative stress might contribute to impairments in cholinergic receptor-linked signaling systems and if intracellular glutathione levels modulated responses to oxidative stress. To do this the activation of the AP-1 and NF-kappaB transcription factors and of the phosphoinositide second-messenger system was measured in human neuroblastoma SH-SY5Y cells after exposure to the oxidants H2O2 or diamide, with or without prior depletion of cellular glutathione. H2O2 concentration-dependently inhibited carbachol-stimulated AP-1 activation and this inhibition was potentiated in glutathione-depleted cells. Carbachol-stimulated NF-kappaB activation was unaffected by H2O2 unless glutathione was depleted, in which case there was a H2O2 concentration-dependent inhibition. Glutathione depletion also potentiated the inhibition by H2O2 of carbachol- or G-protein (NaF)-stimulated phosphoinositide hydrolysis, whereas phospholipase C activated by the calcium ionophore ionomycin was not inhibited. The thiol-oxidizing agent diamide also inhibited phosphoinositide hydrolysis stimulated by carbachol or NaF, and glutathione depletion potentiated the diamide concentration-dependent inhibition. Unlike H2O2, diamide also inhibited ionomycin-stimulated phosphoinositide hydrolysis. Activation of both AP-1 and NF-kappaB stimulated by carbachol was inhibited by diamide, and glutathione depletion potentiated the inhibitory effects of diamide. Thus, diamide inhibited a wider range of signaling processes than did H2O2, but glutathione depletion increased the susceptibility of phosphoinositide hydrolysis and of transcription factor activation to inhibition by both H2O2 and diamide. These results demonstrate that the vulnerability of signaling systems to oxidative stress is influenced by intracellular glutathione levels, indicating that cell-selective susceptibility to inhibition of signal transduction systems by oxidative stress can arise from cellular variations in antioxidant capacity.

Analysis of Variance↗
PubMed1990

Inhibitors of membrane transmethylation reactions prevent the lymphocyte chemokinetic response.

The methylation of membrane phospholipids has been shown to occur following receptor-mediated activation of leukocytes. The present studies show that the human lymphocyte response to two positive chemokinetic signals (bradykinin and lymphocyte chemoattractant factor) can be interrupted by inhibitors of S-adenosyl-L-methionine-mediated transmethylation reactions. The chemokinetic response to the nonphysiologic stimulant colchicine is not affected. We speculate that phospholipid methylation accompanies receptor-mediated lymphocyte migration, and may facilitate activation of second messenger systems.

Adenine↗
PubMed1992

Temporal and spatial modulation of a cytoskeletal antigen during peripheral axonal pathfinding.

A neuron-specific cytoskeletal antigen (5E10), whose expression pattern during initial motoneuron outgrowth into the chick limb suggests that it is playing a role in axon guidance, is described. This antigen, which was shown to be a phosphorylated epitope, probably of the intermediate weight neurofilament protein (NF-M), exhibits a highly stereotyped and spatially heterogeneous pattern of expression. The point of onset of expression, which was abrupt and occurred in the distal axon and base of the growth cone, differed between groups of neurons that projected to different targets. Specifically, expression occurred from positions where previous perturbation experiments suggested that the axons in question would begin responding to specific guidance cues, and it remained high along the axon from this point to the target. Expression of this antigen could also be induced in cultured motoneurons by activating several second messenger systems.

Animals↗
PubMed1992

Regulation of a potassium-selective current in rabbit corneal epithelium by cyclic GMP, carbachol and diltiazem.

The effects of cyclic GMP (cGMP), carbachol and diltiazem on a potassium-selective, delayed-rectifier current in freshly dissociated rabbit corneal epithelial cells were studied using a modified perforated-patch-clamp technique. The current was stimulated by both 500 microM cGMP (2.3-4.5-fold, mean = 2.9) and 250 nM carbachol, a muscarinic agonist (1.12-7.04-fold, mean = 3.8), and the stimulated current was totally blocked by diltiazem (10 microM). The effects of cGMP appeared to be, at least in part, different from those of carbachol as they required the presence of external calcium. Single-channel data suggest that cGMP and carbachol activate the potassium current by increasing the open probability of the channel via a second-messenger system and that the action of diltiazem is probably through a direct blocking effect on the open channel.

Animals↗
PubMed1991

Noradrenergic potentiation of excitatory transmitter action in cerebrocortical slices: evidence for mediation by an alpha 1 receptor-linked second messenger pathway.

Considerable evidence from intact, anesthetized preparations suggests that norepinephrine (NE) can modulate the efficacy of synaptic transmission within local circuits of the mammalian neocortex; i.e. both iontophoretic application of NE and activation of the coeruleocortical pathway are capable of facilitating cortical neuronal responses to non-noradrenergic synaptic inputs and putative transmitter agents. In the present study, the effects of NE on somatosensory cortical neuronal responses to putative excitatory transmitters were characterized using in vitro tissue slice preparations. Somatosensory unit responses to iontophoretic pulses of acetylcholine (ACh) or glutamate (Glu) (10-60 nA; 5-25 s duration) were examined before, during and after a period of continuous NE (1-35 nA; 4-25 min duration) microiontophoresis. Quantitative analysis of per-event histograms indicated that both Glu- and ACh-evoked excitatory discharges were routinely (Glu 94%, n = 54; ACh 67%, n = 9) potentiated above control levels during NE administration. In 8 cells, NE revealed robust excitatory discharges to otherwise subthreshold iontophoretic doses of Glu. The alpha-specific agonist, phenylephrine, mimicked (n = 3), NE-induced potentiation of Glu-evoked discharges whereas the alpha antagonist phentolamine blocked (n = 5) enhancement of these responses. Moreover, activation of protein kinase C by iontophoretic application of phorbol 12,13-diacetate (5-15 nA, n = 4) mimicked the potentiating actions of NE on Glu-evoked excitatory responses. Results from other experiments further indicated that these facilitating actions of NE on Glu-evoked responses do not involve beta receptor activation or intracellular increases in cyclic AMP. In summary, these results demonstrate that NE can facilitate cortical neuronal responses to threshold and subthreshold level applications of putative excitatory transmitter agents. Moreover, it appears that, unlike noradrenergic facilitating influences on GABA-induced inhibition, these actions are mediated by an alpha adrenoceptor mechanism which may be linked to intracellular activation of protein kinase C. Overall, these findings reinforce the idea that noradrenergic modulatory actions on excitatory and inhibitory neuronal responses may involve the activation of separate receptor-linked second messenger systems.

Acetylcholine↗
PubMed1995

Induction of apoptosis in thymocytes: new evidence for an interaction of PKC and PKA pathways.

The second messenger cascades connected to PKC and PKA are involved in the induction of apoptosis. Here we study the interaction of those two second messenger pathways with respect to the induction of apoptosis by stimulation or inhibition. The stimulators used were phorbol dibutyrate for PKC and one of the cAMP agonists Sp-5,6 DCl-cBIMPS or Sp-cAMP for PKA. The inhibitors used were staurosporin for PKC and the cAMP antagonist Rp-cAMPS for PKA. We found a synergism between both second messenger systems with regard to the induction of apoptosis in thymus lymphocytes.

Animals↗
PubMed1998

Defasciculation of neurites is mediated by tenascin-R and its neuronal receptor F3/11.

Fasciculation and defasciculation of axons are major morphogenetic events in the formation of neuronal pathways during development. We have identified the extracellular matrix glycoprotein tenascin-R (TN-R) and its neuronal receptor, the immunoglobulin superfamily recognition molecule F3, as promoters of neurite defasciculation in cerebellar explant cultures. Perturbation of the interaction between these two molecules using both antibodies and an antisense oligonucleotide resulted in increased neurite fasciculation. The domains involved in defasciculation were identified as the N-terminal region of TN-R containing the cysteine-rich stretch and the 4.5 epidermal growth factor-like repeats and the immunoglobulin-like domains of F3. Fasciculation induced by antibodies and the antisense oligonucleotide could be reverted by a phorbol ester activator of protein kinase C, whereas the protein kinase inhibitor staurosporine increased fasciculation. Our observations indicate that defasciculated neurite outgrowth does not only depend on the reduction of the expression of fasciculation enhancing adhesion molecules, such as L1 and the neural cell adhesion molecule (NCAM), but also on recognition molecules that actively induce defasciculation by triggering second messenger systems.

Animals↗
PubMed1988

Forskolin and phorbol esters decrease the same K+ conductance in cultured oligodendrocytes.

Cultured ovine oligodendrocytes (OLGs) express a number of voltage-dependent potassium currents after they attach to a substratum and as they begin to develop processes. At 24-48 hours following plating, an outward potassium current can be identified that represents a composite response of a rapidly inactivating component and a steady-state or noninactivating component. After 4-7 days in culture, OLGs also develop an inward rectifier current. We studied the effects of forskolin and phorbol 12-myristate 13-acetate (PMA) on OLG outward currents. These compounds are known to alter the myelinogenic metabolism of OLGs. PMA, an activator of protein kinase C (PK-C), has been shown to enhance myelin basic protein phosphorylation while forskolin acting on adenylate cyclase, and thereby increasing cAMP, inhibits it. Both forskolin and PMA increase the phosphorylation of 2'3'-cyclic nucleotide phosphodiesterase, an OLG/myelin protein. We found that forskolin decreased the steady-state outward current at 120 mV by 10% at 100 nM, and by 72% at 25 microM from a holding potential of -80 mV. The time course of inactivation of the peak currents was decreased, affecting both the fast and slow time constants. There was no significant change in the steady-state parameters of current activation and inactivation. The effect of forskolin was attenuated when the adenylate cyclase inhibitor adenosine (2 mM) was present in the intracellular/pipette filling solution. The results of PMA experiments were similar to those obtained with forskolin. Whereas the amplitude of the currents in the presence of PMA was reduced by 28% at 1.5 nM and 60% and 600 nM, the decay phase of the peak currents was less affected. The PMA effect could still be seen when the intracellular Ca2+ was reduced to less than or equal to 10 nM with 5 mM BAPTA, but was inhibited when the cells were pre-exposed to 50 microM psychosine, a PK-C inhibitor. It is postulated that the potassium currents in OLG can be physiologically modulated by two distinct second-messenger systems, perhaps converging at the level of a common phosphorylated enzyme or regulatory protein.

Animals↗
PubMed1989

Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: evidence for mediation through the beta-adrenoceptor-coupled cyclic AMP system.

Previous in vivo studies from our laboratory have consistently shown that iontophoretically applied norepinephrine (NE) can potentiate gamma-aminobutyric acid (GABA)-induced depressant responses of cerebrocortical, cerebellar and hypothalamic neurons. Additional experiments have further suggested that this noradrenergic facilitating action is specific for GABA and results from the activation of a beta-type adrenoceptor. The goal of the present studies was to determine if the cAMP second messenger system might also be a component of the mechanism responsible for this NE modulatory action on GABA-mediated inhibition. In one set of in vitro experiments, we examined cerebellar neuronal responses to GABA before, during and after iontophoretic application of NE, 8-bromo-3',5'-cyclic AMP (BcAMP) or 3-isobutyl-1-methyl xanthine (IBMX) or bath application of forskolin (10-30 microM). In a second group of in vivo studies, extracellularly recorded responses of individual cerebellar Purkinje (P) cells to iontophoretic pulses of GABA or beta-alanine were examined before, during and after NE or BcAMP microiontophoresis. In 20 of 25 cerebellar cells recorded from tissue slices, iontophoretically applied NE markedly enhanced responses to GABA in a manner similar to that observed previously in vivo. In these in vitro preparations, bath application of forskolin was also capable of potentiating GABA-induced inhibition in each of 4 cases tested whereas dideoxy-forskolin was not. Iontophoretic application of IBMX further enhanced the facilitating effects of NE on GABA-induced inhibition in 10 of 11 cases tested. Furthermore, under in vitro conditions, BcAMP augmented inhibitory responses to GABA in all cerebellar neurons tested. In the intact rat brain, iontophoretic administration of BcAMP caused a marked NE-like augmentation of P-cell responses to GABA in 73% of the cells tested. As with NE, BcAMP was ineffective in enhancing P-cell inhibitory responses to beta-alanine, an agent which like GABA causes hyperpolarization, by increasing Cl conductance. In summary, these results indicate that a membrane permeant analog of cAMP, a phosphodiesterase inhibitor and an agent which directly activates adenyl cyclase can mimic the previously observed GABA-potentiating actions of NE. Thus, these findings provide further support for the contention that noradrenergic enhancement of GABA inhibition results from a cascade of transmembrane events which includes beta-receptor activation, adenyl cyclase stimulation and increased intracellular production of cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Focal increases in [3H]forskolin and [3H]phorbol 12,13-dibutyrate binding in the rat brain following lesions of the medial septum.

Quantitative autoradiography of [3H]forskolin binding to GS-adenylate cyclase and [3H]phorbol 12,13-dibutyrate (PDBu) binding to protein kinase C (PKC) was examined 21 days following ibotenate lesion of the rat medial septum. A significant reduction (-19%) in [3H]forskolin binding was observed at the lesion site in the medial septum compared to the sham-treated group. A significant increase in [3H]forskolin binding was demonstrated in the polymorph layer of the detante gyrus (19%) in animals with medial septal lesions whilst in all other brain regions, [3H]forskolin binding remained unaltered post-lesion. [3H]PDBu binding was significantly increased in the superficial layers (I-III) of entorhinal cortex (27%) following lesion of the medial septum, and remained unaltered in all other brain regions post-lesion. The nature and location of the alterations (namely elevations) in ligand binding sites remote from the lesioned area are supportive of plastic modifications of second messenger systems following denervation.

Adenylyl Cyclases↗
PubMed1994

Interaction between epidermal growth factor and arginine vasopressin in renal medullary membranes.

1. Epidermal growth factor is a potent mitogen that causes natriuresis, diuresis and inhibition of arginine vasopressin-induced water reabsorption. 2. The aim of this study was to determine any interaction between epidermal growth factor and the V1 (vascular) and/or V2 (antidiuretic) arginine vasopressin receptor subtypes. 3. Radioligand binding displacement assays demonstrated that although arginine vasopressin related peptides displaced both radioligands from renal medullary membranes at low concentrations epidermal growth factor displaced neither. 4. Arginine vasopressin V2 receptor second messenger cyclic adenosine monophosphate (cAMP) production was inhibited by epidermal growth factor (IC50 2 x 10(-7) mol/L) as was sodium fluoride cAMP production but only at much higher concentrations. 5. Therefore the diuretic effect of epidermal growth factor is not via direct antagonism of arginine vasopressin receptors but seems mediated via inhibition of the V2 second messenger system.

Adenylyl Cyclases↗
PubMed1993

Muscarinic receptor regulation and 2nd messenger responses in rat neocortex cultures.

Primary cultures of dissociated cerebral cortex cells were used to characterize the muscarinic acetylcholinergic receptors (mAChR) present and to study receptor down-regulation and receptor mediated 2nd messenger responses induced by muscarinic agonists. Binding of the hydrophilic antagonist [3H]N-methyl scopolamine ([3H]NMS) to the cultured cells was saturated after one hour at 4 degrees C with a Kd of 93 pM and a Bmax of 958 fmol/mg protein. Competition binding studies with several antagonists and agonists indicated that the mAChR present in the culture were of a mixed M1/M3 subtype. The number of muscarinic receptors at the cell surface decreased by 60% after one hour pre-incubation of the cultures with 10 microM carbachol or oxotremorine. After down-regulation with carbachol affinity for pirenzepine was decreased, while low affinity sites for 4-DAMP were lost, indicating that especially M1 subtypes are sensitive to this type of regulation. Carbachol and oxotremorine-M induced a 2-3 fold increase in phosphatidyl inositide (PI) turnover, which was blocked with high affinity by both pirenzepine and 4-DAMP. Down-regulation of the mAChR and stimulation of PI-turnover by agonists with different potency and intrinsic activity appeared highly correlated. These data suggest that activation of the PI second-messenger system is involved in the desensitization and down-regulation of the muscarinic acetylcholine receptor.

Animals↗
PubMed1991

Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation.

Sphingosine, a metabolite of membrane sphingolipids, regulates proliferation of quiescent Swiss 3T3 fibroblasts (Zhang, H., N. E. Buckley, K. Gibson. and S. Spiegel. 1990. J. Biol. Chem. 265:76-81). The present study provides new insights into the formation and function of a unique phospholipid, a metabolite of sphingosine, which was unequivocally identified as sphingosine-1-phosphate. The rapid increase in 32P-labeled sphingosine-1-phosphate levels induced by sphingosine was concentration dependent and correlated with its effect on DNA synthesis. Similar to the mitogenic effects of sphingosine, low concentrations of sphingosine-1-phosphate stimulated DNA synthesis and induced pronounced morphological alterations. Both sphingosine and sphingosine-1-phosphate stimulated DNA synthesis in cells made protein kinase C deficient by prolonged treatment with phorbol ester and sphingosine still elicited similar increases in sphingosine-1-phosphate levels in these cells. Although both sphingosine and sphingosine-1-phosphate acted synergistically with a wide variety of growth factors, there was no additive or synergistic effect in response to a combination of sphingosine and sphingosine-1-phosphate. Using a digital imaging system for measurement of calcium changes, we observed that both sphingosine and sphingosine-1-phosphate are potent calcium-mobilizing agonists in viable 3T3 fibroblasts. The rapid rise in cytosolic free calcium was independent of the presence of calcium in the external medium, indicating that the response is due to the mobilization of calcium from internal store. Our results suggest that sphingosine-1-phosphate may be a component of the intracellular second messenger system that is involved in calcium release and the regulation of cell growth induced by sphingosine.

Animals↗
PubMed2005

Phosphodiesterase inhibitors for cognitive enhancement.

An effective treatment for age-related cognitive deficits remains an unmet medical need. Currently available drugs for the symptomatic treatment of Alzheimer's disease or other dementias have limited efficacy. This may be due to their action at only one of the many neurotransmitter systems involved in the complex mechanisms that underlie cognition. An alternative approach would be to target second messenger systems that are utilized by multiple neurotransmitters. Cyclic adenosine monophosphate (cAMP) is a second messenger that plays a key role in biochemical processes that regulate the cognitive process of memory consolidation. Prolongation of cAMP signals can be accomplished by inhibiting phosphodiesterases (PDEs). Eleven PDE families, comprised of more than 50 distinct members, are currently known. This review summarizes the evidence demonstrating that rolipram, a selective inhibitor of cAMP-selective PDE4 enzymes, has positive effects on learning and memory in animal models. These data provide support for the general approach of second messenger modulation as a potential therapy for cognitive dysfunction, and specifically suggest that PDE4 inhibitors may have utility for improving the symptoms of cognitive decline associated with neurodegenerative and psychiatric diseases.

Animals↗
PubMed1989

Agonist binding to M1 muscarinic receptors is sensitive to guanine nucleotides.

Putative M1 (high-affinity pirenzepine) muscarinic receptors in rabbit hippocampal membranes, treated with 0.1 mM N-ethylmaleimide (NEM), were selectively labeled with [3H]pirenzepine. A single class of binding sites was labeled with a Kd of 3.4 nM, consistent with the pharmacologically-defined M1 subtype of muscarinic receptors. While full muscarinic agonists bound to high- and low-affinity states of [3H]pirenzepine-labeled M1 sites with a KL/KH ratio of approximately 100, the ratio for partial muscarinic agonists was approximately 10. The high-affinity binding of all agonists tested required divalent cations, and was interconverted to low-affinity binding in the presence of the non-hydrolyzable GTP analogue, guanylyl imidodiphosphate (GppNHp). Direct labeling of the high-affinity agonist state of M1 receptors was achieved with 5 nM [3H]oxotremorine-M by selectively uncoupling the high-affinity agonist state of M2 (low-affinity pirenzepine) receptors with NEM. The rate of dissociation of [3H]Pxotremorine-M from M1 receptors was accelerated 6-fold by GppNHp. These results provide further evidence which suggests that putative M1 muscarinic receptors activate second messenger systems by coupling to NEM-insensitive guanine nucleotide-binding proteins.

Animals↗