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Results for “Second Messenger Systems”

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At least 19 recordsLinked to original sources
PubMed1992

Mediation of serotonin hyperalgesia by the cAMP second messenger system.

In this study we have evaluated the second messenger system that might couple 5-HT1A receptor activation to produce peripheral hyperalgesia. The intradermal injection of the serotonin (5-hydroxytryptamine; 5-HT) receptor agonist for the 1A receptor subset (5-HT1A), (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide (8-OH DPAT) produces a dose-dependent hyperalgesia which was attenuated by a cAMP kinase inhibitor (the R-isomer of cyclic adenosine-3'-5'-monophosphate), but prolonged by the inhibition of endogenous phosphodiesterase by rolipram, supporting a role for the cAMP second messenger system. The 5-HT1A receptor agonist, 8-OH-DPAT, and the adenyl cyclase activator, forskolin administered together, produced an additive hyperalgesia, suggesting that the 5-HT1A receptor in peripheral terminals of the primary afferent neurons is positively coupled to the cAMP second messenger system in producing hyperalgesia. The inability of pertussis toxin to inhibit 8-OH DPAT-induced hyperalgesia further supports this hypothesis. The coupling of the 5-HT1A receptor to the cAMP second messenger system appears to be through guanine regulatory proteins since guanosine 5'-O-(3-thiotriphosphate) and cholera toxin both markedly enhanced 8-OH DPAT hyperalgesia. In further support of the role of guanine nucleotide regulatory proteins, guanosine 5'-O-(2-thiodiphosphate), as well as activators of inhibitory guanine regulatory proteins (the mu-opioid agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, and the adenosine A1 agonist, N6-cyclopentyladenosine, significantly attenuated 8-OH DPAT hyperalgesia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Phospholipid metabolism and second messenger system after brain ischemia.

To evaluate possible involvement of phospholipid metabolism and related second messenger systems in the selective neuronal damage after ischemia, we measured changes of polyphosphoinositides (PPIs) and free fatty acids (FFAs) in a model of 5-min or 10-min ischemia and reperfusion in gerbils. The binding activity of 3H-phorbol 12,13-dibutyrate (PDBu) for protein kinase C (PKC) and 3H-inositol 1,4,5-triphosphate (IP3) for IP3 receptors was demonstrated autoradiographically. Induction of 70 KDa heat shock protein (HSP70) mRNA and amyloid precursor protein (APP) mRNA was also examined using Northern blot analysis. In the parietal cortex (an area resistant to transient ischemia), PPIs decreased during ischemia and recovered rapidly after reperfusion. However, recovery did not occur in the hippocampal CA1 area (an area more vulnerable to transient ischemia). In the cortex, arachidonic acid (AA) increased during ischemia and returned to baseline by 7 days after reperfusion; in the CA1 area, the AA level remained elevated even after 7 days of reperfusion. PDBu binding decreased in CA1 cells after 2 days of reperfusion. IP3 binding began to decrease at 5 hr of reperfusion, which is far earlier than either the onset of decreased PDBu binding or the observation of neuronal damage by light microscopy. The induction of HSP70 mRNA occurred, but the induction of APP mRNA did not. Regional differences in the induction of HSP70 mRNA were found; CA1 cells produced less HSP70 mRNA than cortical cells 8 hr after transient ischemia. These results suggest that CA1 cell membranes may not recover after transient ischemic attack, and that the membranes of the endoplasmic reticulum, which have IP3 receptors, may undergo alterations earlier than cytoplasmic membranes. The variable induction of HSP70 mRNA may be related to regional differences in vulnerability in cortical and hippocampal CA1 cells after transient ischemia. Involvement of excitatory neurotransmission in the induction of HSP70 has been suggested. The combined data may support a role for inositol phospholipid metabolism, changes in related second messenger systems, and induction of HSP70 in the excitotoxic mechanism of hippocampal CA1 neuronal damage, death, and repair.

Amyloid beta-Protein Precursor↗
PubMed1992

Age-related alterations in second-messenger systems in the gerbil brain: autoradiographic analysis and effect of vinconate.

Age-related alterations in binding sites of major second-messenger systems in the gerbil brain were analyzed by receptor autoradiography using [3H]phorbol 12,13-dibutyrate (PDBu), and [3H]inositol 1,4,5-trisphosphate (IP3). In middle-aged gerbils (16 months old), the reduction of PDBu-binding sites was noticed in various brain regions compared with young animals (4 weeks old). By contrast, the elevation of IP3-binding sites was seen in most of brain regions except for the reduction in the cerebellum in the middle-aged animals. Chronic treatment with vinconate partly regulated the age-related changes in the binding sites of these second messengers. The result demonstrates the age-related alterations in the binding sites of an intracellular second-messenger system. Furthermore, they suggest that vinconate partly modulates the age-related alterations in the bindings of second messengers.

Aging↗
PubMed1991

Autoradiographic analysis on second-messenger systems and local cerebral blood flow in ischemic gerbil brain.

Alterations of the second-messenger systems, adenylate cyclase (AC) and protein kinase C (PKC), and local cerebral blood flow (lCBF) were evaluated during experimental cerebral ischemia in gerbils employing a quantitative autoradiographic method, which permitted these three parameters to be measured in the same brain. Ischemia was induced by occlusion of the right common carotid artery for 6 h. Animals attaining more than 5 in their ischemic scores were utilized for further experiments. At the end of ischemia, lCBF was measured by the [14C]iodoantipyrine method. The AC and PKC activities were estimated by the autoradiographic technique developed in our laboratory using [3H]forskolin (FK) and [3H]phorbol-12,13-dibutyrate (PDBu), respectively. The lCBF fell below 10 ml/100 g/min in most cerebral regions on the ligated side. The greatest reduction in FK binding was noted in the olfactory tubercle, caudate-putamen, and globus pallidus, followed by the hippocampus and cerebral cortices. The FK binding tended to be low at lCBF less than 20 ml/100 g/min in the cerebral cortices. However, the PDBu binding was relatively well preserved in each cerebral structure, and no significant correlation between lCBF and PDBu binding was noted in the cerebral cortices. The AC system may thus be vulnerable to ischemic insult over extensive brain regions, while the PKC system may be relatively resistant to ischemia.

Adenylyl Cyclases↗
PubMed1991

Opioid receptor-coupled second messenger systems.

Although pharmacological data provide strong evidence for different types of opioid receptors (e.g., mu, delta, and kappa), they share many common properties in their ability to couple to second messenger systems. All opioid receptor types are coupled to G-proteins, since agonist binding is diminished by guanine nucleotides and agonist-stimulated GTPase activity has been identified in several preparations. Moreover, all three types inhibit adenylyl cyclase. This second messenger system has been identified for opioid receptors in both isolated brain membranes and in transformed cell culture. Studies with chronic treatment with opioid agonists suggest that the coupling of receptors with G-proteins and second messenger effectors may play important roles in development of opioid tolerance.

Animals↗
PubMed1992

Interleukin 6 modulation of second messenger systems in anterior pituitary cells.

We investigated the effect of interleukin-6 (IL-6) on second messenger systems in anterior pituitary (AP) cells. The acute exposition of membranes derived from the pituitary gland to IL-6 did not modify basal and forskolin-stimulated adenylate cyclase (AC) activity, as well as inositol phosphate (IP) production and free [Ca(++)]i. Preincubation of AP cells with IL-6 for 20 min did not affect basal second messengers levels, while completely abolished the stimulation by VIP of AC activity, partially inhibited forskolin-stimulated cAMP formation and reduced TRH-stimulated IP production. Finally, the pretreatment of AP cells for 20 min with IL-6 also reduced the TRH-induced rise in free [Ca(++)]i.

Adenylyl Cyclases↗
PubMed1992

The effect of active serum albumin on PC12 cells: I. Neurite retraction and activation of the phosphoinositide second messenger system.

Vertebrate blood sera contain a factor that triggers oscillatory chloride currents in Xenopus oocytes through activation of the phosphoinositide/Ca2+ second system. The active serum component consists of lipids bound to an isoform of serum albumin that we have named active serum albumin (ASA). In undifferentiated PC12 cells, micromolar concentrations of ASA inhibit the early morphological changes induced by NGF, whereas in differentiated PC12 cells ASA caused a rapid withdrawal of neurites, which was reversible and dependent upon culture age. In contrast to normal serum, plasma and thrombin did not cause neurite retraction. Preincubation of ASA with monospecific antibodies to serum albumin suppressed its ability to induce neurite retraction in a dose dependent fashion. As in the oocyte, ASA activated the phosphatidylinositol second messenger system of PC12 cells, causing a several fold increase in Ins1,4,5P3 levels within minutes of application. The Ins1,4,5P3 increase was also blocked, in a titratable fashion, when ASA was preincubated with monospecific antibodies to serum albumin. This suggests that ASA-induced neurite retraction in PC12 cells may depend, at least in part, on activation of the phosphatidylinositol second messenger system. Results involving albumin-depleted sera show that ASA is the main factor responsible for serum vulnerability of neurites in PC12 cells. These findings point to some limitations in the use of serum in culture media, and raise the possibility that the serum factor may impair neuronal plasticity in disorders that are accompanied by the activation of blood coagulation together with a breakdown of the blood-brain barrier.

Animals↗
PubMed1992

Cholinergic regulation of the phosphoinositide second messenger system in the guinea pig organ of Corti.

The effect of cholinergic agents on the phosphoinositide second messenger system was investigated in the cochlea of the adult guinea pig in vivo and in vitro. In vivo, phospholipids were labeled with [32P]-orthophosphate by perilymphatic perfusion and their hydrolysis assayed in 'chase' experiments with non-radioactive orthophosphate. Carbachol (1 mM) reduced the content of 32P-labeled phosphatidylinositol 4,5-bisphosphate in the organ of Corti from 31% to 21% of total 32P-lipids, indicating stimulated hydrolysis. The pharmacology of this effect was studied in detail in vitro via the release of inositol phosphates from phosphoinositides pre-labeled with 3H-inositol. Release was increased 2-fold by 1 mM carbachol, 1.6-fold by 1 mM muscarine, but was unaffected by dimethylphenylpiperazinium; the stimulation was blocked by 1 microM atropine but not mecamylamine. These responses indicate the coupling of phosphoinositides to a muscarinic receptor. Furthermore, stimulated inositol phosphate release was higher in the base of the organ of Corti than in the apex which correlates with the increased cholinergic efferent innervation of outer hair cells in the basal region. These results suggest that muscarinic-stimulated inositol phosphate release occurs at the level of the outer hair cell and thus may have an important modulatory role in auditory transduction.

Animals↗
PubMed1991

The effects of maternal ethanol exposure on neurotransmission and second messenger systems: a quantitative autoradiographic study in the rat brain.

The effects of maternal ethanol exposure on neurotransmission and second messenger systems were examined in rats using histochemistry and in vitro autoradiography. Thirty % ethanol was administered to pregnant rats from gestational day 7 to the day of delivery. Quantitative autoradiography was used to map muscarinic cholinergic, dopamine D2, adenosine A1, and inositol 1,4,5-trisphosphate binding sites, as well as to localize adenylate cyclase and protein kinase C. We found no difference in the patterns of staining with acetylcholinesterase and Timm's stain between control and prenatally ethanol-exposed rats on postnatal day (PN) 30. In the ethanol-exposed rats, [3H]forskolin binding sites were increased during early development in the CA1 subfield of the hippocampus and the occipital cortex; [3H]phorbol ester binding sites were increased in the cortex, striatum, and hippocampus; hippocampal muscarinic cholinergic sites were increased on PN4 and 30; adenosine A1 binding was reduced on PN10 in most regions examined, but was increased in the CA1 subfield on PN30; dopamine D2 receptor levels were significantly reduced on PN30 in the striatum; and IP3 receptors were decreased in most regions studied, but particularly in the cerebellum. Thus, some of these changes were transient and others were long-lasting. Although histopathological abnormalities were minimal, the alterations of binding sites in the cerebellum (the coordination center) and in the hippocampus (related to memory and learning) that were detected may contribute to the behavioral and mental deterioration seen in the fetal alcohol syndrome.

Animals↗
PubMed1991

Alteration of second messenger systems after transient cerebral ischemia in gerbils: protective effect of pentobarbital and an autoradiographic analysis.

The postischemic alteration of second messenger systems in the gerbil brain was analyzed by receptor autoradiography using [3H]phorbol 12,13-dibutyrate (PDBu) and [3H]inositol 1,4,5-trisphosphate (IP3). The alteration of the [3H]PDBu binding in striatum and hippocampus was milder than that of the [3H]IP3 binding 5 h and 7 days after 10-min ischemia. The administration of pentobarbital prevented a decrease in the [3H]IP3 binding sites in all areas 5 h and 7 days after ischemia. These results suggest that the disruption of intracellular calcium homeostasis may play an important factor in ischemic brain damage.

Animals↗
PubMed1991

Hepoxilins modulate second messenger systems in the human neutrophil.

In this chapter, we will review recent findings which implicate the hepoxilins as modulators of second messenger systems in the human neutrophil. We have shown that the hepoxilins affect calcium homeostasis in the cell and that they stimulate the release of arachidonic acid and diradylglycerol but not inositol phosphate indicating a mode of action for these 12-lipoxygenase metabolites that is independent of phospholipase C activation. In fact lipid analyses indicate that the phospholipid affected by the hepoxilins is phosphatidyl choline, and that this phospholipid is hydrolyzed by a phospholipase D. These findings indicate that the hepoxilins, which are formed by the platelet as well as the neutrophil, may affect neutrophil activation through a potential cell-cell interaction in the circulation or at pathologic sites to initiate or potentiate the inflammatory process.

8,11,14-Eicosatrienoic Acid↗
PubMed1991

Arteriolar vasodilatation in frog skeletal muscle in vivo: modification of second messenger systems.

This study was concerned with the role of cyclic nucleotides in the post-junctional vasodilatation mechanism. Interventions with second messenger systems involving cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), allowed the role of these nucleotides in vascular smooth muscle to be evaluated in the autoperfused, transparent frog muscle, m. cutaneous pectoris. The microcirculation was observed by intravital microscopy, and arteriolar diameters were continuously recorded. Pre- and post-junctional effects were distinguished by comparing results in control frogs with those obtained in frogs that had been chemically sympathectomized with either 6-hydroxydopamine or tetrodotoxin. Arterioles that were pre-contracted with adrenaline dilated in response to topical application of forskolin or sodium nitroprusside, which are direct activators of intracellular adenylate cyclase and guanylate cyclase, respectively. Arterioles were also dilated by 3-isobutyl-1-methylxanthine (IBMX), which is a non-selective inhibitor of cyclic AMP- and cyclic GMP-phosphodiesterase, and by rolipram, which is a selective inhibitor of the calcium-independent cyclic AMP-phosphodiesterase. Dibutyryl-cyclic AMP and dibutyryl-cyclic GMP also caused vasodilatation. These results indicate that in vascular smooth muscle, intracellular mechanisms involving cyclic nucleotides (cyclic AMP and cyclic GMP) are important in vasodilatation. They may act in conjunction with pre-junctional inhibitory mechanisms on sympathetic nerves.

Animals↗
PubMed1991

The Ca2+ second messenger system and interleukin-1-alpha modulation of hepatic gene transcription and mitochondrial fat oxidation.

Cytokines have been implicated in the modulation of fat metabolism after sepsis. Carnitine palmitoyltransferase (CPT), the regulatory enzyme of hepatic mitochondrial long-chain fatty-acid oxidation, is involved in the control of hepatic fat oxidation in sepsis. Using either H4IIe rat hepatoma cells or rat hepatocytes in primary culture, we tested the hypothesis that interleukin-1-alpha (IL-1 alpha) would modulate CPT transcription (CPT mRNA), CPT translation (35S-methionine CPT protein incorporation), and hepatic mitochondrial oxidation of 1-Carbon 14-labeled (14C) palmitate to ketone bodies (acid soluble products). We showed that IL-1 alpha significantly increased CPT mRNA, 35S-methionine incorporation CPT protein, and hepatic mitochondrial oxidation of 1-14C-palmitate to acid soluble products. We further hypothesized that the Ca2+ second messenger system may play a role in the IL-1 alpha induction of hepatic CPT gene transcription. We showed that either calcium ionophore (A23187) or phorbol myristate acetate increased CPT gene transcription and that either calcium chelation, protein kinase C inhibition (acridine orange), or chronic exposure to phorbol myristate acetate significantly inhibited IL-1 alpha induction of CPT mRNA. We conclude that the IL-1 alpha increases in hepatic mitochondrial fatty-acid oxidation may be, in part, secondary to increased CPT gene transcription and translation and that the Ca2+ second messenger system may play an important role in IL-1 alpha induction of CPT gene transcription.

Animals↗
PubMed1991

Autoradiographic analysis of second-messenger systems in the gerbil hippocampus following repeated brief ischemic insults.

Using [3H]inositol 1,4,5-triphosphate (IP3), [3H]phorbol 12,13-dibutyrate (PDBu) and [3H]forskolin, we performed quantitative autoradiography to determine sequential alterations in second-messenger systems in the gerbil hippocampus following repeated brief ischemic insults. Changes following three 2-min ischemic insults were compared with those following single 2- or 6-min ischemia. [3H]IP3 binding was extremely sensitive to ischemic insult, and more than 80% of the binding sites were lost after destruction of CA1 pyramidal cells following 6-min ischemia and three 2-min ischemic insults. Furthermore, a 30% reduction was observed after 2-min ischemia which leads to no neuronal loss. [3H]PDBu binding in the CA1 subfield decreased by 1 day after three 2-min ischemic insults and by 4 days after 6-min ischemia, and 40-50% reductions were observed at 1 month. In contrast, [3H]forskolin binding was relatively preserved. [3H]PDBu and [3H]forskolin binding transiently increased early in the reperfusion period. We also observed a difference in the pattern and severity of alterations between repeated ischemic insults and single ischemia.

Animals↗
PubMed1992

Activation of cyclic AMP second messenger system stimulates secretion of beta-endorphin from fetal hypothalamic cells.

Relatively little is known about physiological regulators of hypothalamic beta-endorphin (END) secretion and mechanisms by which they stimulate secretion. We sought to determine whether activation of the cyclic AMP (cAMP) second messenger pathway was involved in stimulating hypothalamic beta-END secretion from dissociated fetal hypothalamic cells in culture. Forskolin (FSK), a direct activator of adenylate cyclase which stimulates cAMP formation, stimulated immunoreactive (IR)-beta-END secretion. Because FSK can also stimulate independent of increased cAMP formation, we studied dibutyryl cAMP and 8-bromo-cAMP, analogues of cAMP, which also stimulated IR-beta-END secretion. From these studies we conclude: (1) activation of the cAMP second messenger system stimulates IR-beta-END secretion from hypothalamic cells and supports the rationale that endogenous regulators which stimulate this pathway could be involved in the physiological regulation of hypothalamic beta-END secretion; (2) coupling between the cAMP second messenger pathway and stimulation of hypothalamic beta-END secretion which is presumably present at maturity (adulthood) originates at early stages of development (fetal life).

Animals↗
PubMed1992

Induction of tolerance to ischemia: alterations in second-messenger systems in the gerbil hippocampus.

Preconditioning the brain with sublethal ischemia protects against neuronal damage following subsequent ischemic insult. Using [3H]inositol 1,4,5-triphosphate (IP3), [3H]phorbol 12,13-dibutyrate (PDBu), [3H]cyclic adenosine monophosphate (cAMP) and [3H]rolipram, we performed quantitative autoradiography to determine postischemic alterations in second-messenger systems in the gerbil hippocampus following preconditioning the brain with sublethal ischemia. At 7 days of reperfusion, no alterations were observed in brains subjected to 2 min of forebrain ischemia which produced no neuronal damage. However, 3-min ischemia caused a 75% reduction in [3H]IP3 binding (p < 0.01 vs. control) and 15-25% reductions in [3H]forskolin (p < 0.01 vs. control), [3H]cAMP (p < 0.05 vs. control), and [3H]rolipram (p < 0.01 vs. control) binding in the CA1 subfield coincident with histopathological CA1 pyramidal cell destruction, but no significant alterations in [3H]PDBu binding. Preconditioning the brain with 2 min of ischemia followed by 4 days of reperfusion prevented both histopathological cell death and the reductions in binding following subsequent 3 min of ischemia. Interestingly, [3H]IP3 and [3H]rolipram binding in CA1 showed a transient reduction, by 30% and 20% (both p < 0.01 vs. control), respectively, in the early reperfusion period. This downregulation of the IP3 system may play a role in the protection against cell death.

Animals↗
PubMed1992

The calcium second messenger system in bipolar disorders: data supporting new research directions.

Studies of aberrations in second messenger function may help to elucidate some of the multiple complex neurobiological alterations in bipolar affective disorders. The phosphatidylinositol and calcium ion (Ca2+) second messengers are of particular interest because of evidence of hyperactivity of these signaling mechanisms in both mania and bipolar depression and of their normalization by lithium and other mood-stabilizing treatments. Because the intracellular Ca2+ signal has a biphasic action, a single aberration could explain diverse clinical manifestations of the same illness, and a single action on the messenger could explain the biphasic actions of many treatments for bipolar disorders.

Bipolar Disorder↗
PubMed1991

Alterations of functional glucose use and ligand binding to second messenger systems following unilateral orbital enucleation.

Quantitative autoradiography was used to examine the effect of lesioning a well-defined glutamatergic system (retinofugal fibres) on [3H]forskolin binding to Gs-adenylate cyclase and [3H]PDBu (phorbol-12,13-dibutyrate) binding to protein kinase C (PKC) in the rat visual system at 1, 5, 10 and 20 days after unilateral orbital enucleation. Local cerebral glucose utilisation was determined in the same animals using quantitative [14C]2-deoxyglucose autoradiography. At 5 days post-lesion, [3H]forskolin binding sites were significantly reduced in the visually-deprived superior colliculus (-14 +/- 1%) and dorsal lateral geniculate body (-8 +/- 2%), and these reductions persisted until 20 days post-lesion. There were no significant alterations in the amount of [3H]PDBu binding in any region in the visually-deprived hemisphere following enucleation. Function-related glucose use was significantly reduced throughout the visual pathway after enucleation. In this study, there was no conclusive evidence of plastic modifications of second messenger systems in the rat visual system despite a general depression of visual function following lesion of retinofugal fibres.

Adenylyl Cyclases↗