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At least 19 recordsLinked to original sources
PubMed1982

Some theoretical questions of the peptide and steroid hormone regulation. Part II.: The second messenger system.

The "second messenger system" has been analysed regarding its possibilities for containing and transferring highly specific molecular, biological information. Very heterogeneous molecules were found behind the different - cyclase, diesterase, kinase,... - activities of the system, whereas the connection realized between them by cyclic nucleotides was very poor. So, I constructed a theoretical model mostly on the basis of real and known experimental facts to resolve this obvious contradiction and make the second messenger system adequate as a highly specific biological informational channel.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2002

The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system.

Lipid second messengers, particularly those derived from the polyphosphoinositide cycle, play a pivotal role in several cell signaling networks. Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that have been implicated in a plethora of cell functions. One of the best-characterized targets of PI3K lipid products is the serine/threonine protein kinase Akt. Recent findings have implicated Akt in cancer progression because it stimulates cell proliferation and suppresses apoptosis. Evidence accumulated over the past 15 years has highlighted the presence of an autonomous nuclear inositol lipid metabolism, and suggests that lipid molecules are important components of signaling pathways operating within the nucleus. PI3Ks, their lipid products, and Akt have also been identified at the nuclear level. In this review, we shall summarize the most updated findings about these molecules in relationship with the nuclear compartment and provide an overview of the possible mechanisms by which they regulate important cell functions.

Animals↗
PubMed1987

Beyond receptors: multiple second-messenger systems in brain.

Second-messenger systems play a major role in mediating neurotransmitter actions. In recent years our understanding of the organization and function of two prominent second-messenger systems has progressed rapidly--the adenylate cyclase and phosphoinositide systems. Guanosine triphosphate-binding proteins, which are especially abundant in brain, couple transmitter receptors to the key second-messenger generating enzymes in both of these systems. Whereas activation of adenylate cyclase produces a single intracellular messenger, cyclic AMP, stimulation of the phosphoinositide system generates at least two, inositol trisphosphate and diacylglycerol. Inositol trisphosphate mobilizes calcium from intracellular stores, and diacylglycerol, like cyclic adenosine monophosphate, activates a phosphorylating enzyme, protein kinase C. These second-messenger systems are particularly enriched in the brain where they modulate many aspects of synaptic transmission.

Adenylyl Cyclases↗
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↗
PubMed1993

Carbon-11-forskolin: a ligand for visualization of the adenylate cyclase-related second messenger system.

To visualize the adenylate cyclase (AC)-related second messenger system, [11C]forskolin, [11C]1-acetyl-7-deacetylforskolin, [11C]1,9-dideoxyforskolin and [11C]1-deoxyforskolin were synthesized by acetylation of the respective deacetyl-precursors using [11C]acetylchloride and dimethylaminopyridine. The radiochemical yield of [11C]forskolin, [11C]1-acetyl-7-deacetylforskolin, [11C]1,9-dideoxyforskolin and [11C]1-deoxyforskolin calculated from trapped [11C]CO2 were 5%, 10%, 15% and 18%, respectively. Since the 1- and 9-OH groups on the forskolin structure are critical for specific binding to AC (active type), we considered [11C]1-acetyl-7-deacetylforskolin, [11C]1,9-dideoxyforskolin and [11C]1-deoxyforskolin to be nonspecific forskolin analogs. A comparative study of [11C]forskolin and its analogs on the n-octanol/phosphate buffer (pH 7.4) partition ratio showed that [11C]1-acetyl-7-deacetylforskolin has similar physical properties to [11C]forskolin. In the mouse heart, kidneys, liver and lungs, more [11C]forskolin accumulated than [11C]1-acetyl-7-deacetylforskolin. Moreover, simultaneous [11C]forskolin with forskolin (10 micrograms) administration reduced the accumulation of [11C]forskolin particularly in the heart to the level of [11C]1-acetyl-7-deacetylforskolin. These results indicate that [11C]forskolin would be a useful imaging agent for the AC-related second messenger system.

Adenylyl Cyclases↗
PubMed1995

Effects of general anaesthetics on second messenger systems.

This paper focuses on the potential role of second messenger systems as general anaesthetic targets. Intracellular free calcium, cyclic nucleotides (cAMP, cGMP), inositol polyphosphates, the protein kinase-activating second messenger diacylglycerol, and the transducing G proteins involved in receptor-coupled second messenger pathways have important functions in the neurone that make them promising candidates for sites of relevant anaesthetic actions. To date, however, only distinct members of the heterogeneous family of voltage-operated Ca2+ channels (T and certain sensitive L type channels) and particularly Ca2+ permeable ligand-activated receptor channels, such as the nicotinic acetycholine receptor or the N-methyl-D-aspartate receptor, have been identified as sensitive to the action of general anaesthetics (volatile anaesthetics, barbiturates, ketamine). Conflicting results have been reported on interactions of general anaesthetics with G proteins and their respective second messenger systems. Thus, based on the little work done so far, the receptor-coupled second messengers cannot be considered very convincing candidates for anaesthetic sites. Nevertheless, they remain a challenging area for future research.

Anesthetics, General↗
PubMed1994

Effect of triamcinolone on parathyroid hormone-stimulated second messenger systems and phosphate transport in opossum kidney cells.

Although PTH is known to stimulate both the adenylate cyclase/protein kinase-A system and the phospholipase-C/protein kinase-C second messenger systems, the relative roles of these second messenger pathways remain unclear. The present studies were designed to examine the effect of triamcinolone on PTH-stimulated second messenger systems and phosphate transport in confluent cultures of opossum kidney cells. Triamcinolone was added to these cultures at a concentration of 10 nM for 24-48 h. Neither cell number nor protein content was changed by this treatment. The addition of triamcinolone did not alter PTH receptor binding or competitive displacement radioligand binding assay curves. PTH-stimulated cAMP generation and activation of protein kinase-A were not altered by triamcinolone. The glucocorticoid, however, increased basal phosphate uptake from 1.0 +/- 0.1 to 1.28 +/- 0.1 pmol/5 min.culture (P < 0.01). Phosphate transport was significantly decreased by PTH (0.01 nM) in the triamcinolone-treated cultures, but not in control cultures. Phosphate uptake in the presence of maximal doses of PTH was similar in both control and triamcinolone-treated cultures. Thus, the PTH-responsive component of phosphate transport was preserved, and the threshold dose for the effect of PTH was reduced after treatment with triamcinolone. Studies were then performed to evaluate the alternate second messenger pathway. In control cultures, PTH rapidly increased the level of diglyceride mass, as measured by diglyceride kinase assay, from 0.18 +/- 0.01 to a peak of 0.26 +/- 0.02 mol/100 mol total phospholipid (P < 0.002), 1 min after addition of the hormone. Triamcinolone pretreatment for 48 h, however, elevated the basal diglyceride levels, but the increase after the addition of PTH was totally abolished. The absence of an increase in diglyceride upon stimulation with PTH correlated with elimination of the PTH-stimulated increase in the activity of particulate protein kinase-C. Thus, in triamcinolone-treated cells, the effect of PTH on phosphate transport was preserved, and the threshold dose of PTH-induced alteration in phosphate transport was reduced in the absence of stimulation of this alternate second messenger pathway. These data show that triamcinolone in opossum kidney cells does not alter PTH activation of the cAMP/protein kinase-A system, but eliminates the increase in diglyceride and the activation of protein kinase-C in response to PTH. These studies emphasize the major role of the protein kinase-A system in the regulation of phosphate transport by PTH.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Second messenger systems in Tourette's syndrome.

Abnormalities within second messenger systems have been hypothesized as the underlying pathophysiologic mechanism in a variety of neuropsychiatric disorders. In the Gilles de la Tourette syndrome (TS) prior studies have shown that the concentration of adenosine 3',5'-monophosphate (cAMP) is reduced in cortical and putamen brain regions. In this study, postmortem cortical tissues from 4 adults (mean age 59.5 years) with the lifetime diagnosis of TS and 5 controls (mean age 63.8 years) were analyzed for functional activities within the cAMP and phosphoinositide systems. In addition, plasma cAMP was quantified in children with TS (n = 33) and controls (n = 17). In frontal (A4, A6) and occipital (A17) cortical tissues there were no significant differences for adenylyl cyclase activity whether assayed under basal conditions or after stimulation with GTP gamma S (a non-hydrolyzable GTP analog), forskolin (a selective enzyme stimulator), or (-)-isoproterenol (a beta-adrenergic agonist). D2 receptor activation (quinpirole) and assessment of the inhibitory guanine nucleotide protein also showed no significant alterations in TS samples. Activity of cAMP phosphodiesterase was increased insignificantly in A4 and A17 TS brain regions. Plasma concentrations of cAMP in plasma were similar in children with TS (135.4 +/- 8.3 pmol/ml) and controls (132.6 +/- 7.9 pmol/ml). Postmortem membrane receptor binding for markers within the phosphoinositide (PI) system showed that TS samples had increased [3H]phorbol ester binding to protein kinase C sites in area A17, but normal binding in A4. In contrast, [3H] inositol 1,4,5-triphosphate binding to IP3 receptors showed no significant changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1989

New tools for the localization of second messenger systems.

1. Probes available for the localization of components of second messenger systems include G-protein oligonucleotides which have been used to produce cDNA probes to label G-protein mRNA by in situ hybridization histochemistry. 2. Enzymes involved in second messenger responses have been labelled with [3H]-forskolin (Gs-linked adenylate cyclase), [3H]-cAMP (cAMP-dependent protein kinase) and [3H]-PDBu2 (protein kinase C). 3. [3H]-Inositol 1,4,5 trisphosphate labels a site on sarcoplasmic reticulum believed to trigger Ca2+ release. 4. These probes allow the comparison of location of receptors and second messengers and the examination of changes in second messenger systems with drug treatment and disease.

Animals↗
PubMed1998

Multiple second-messenger system modulation of voltage-activated calcium currents in teleost retinal horizontal cells.

Two voltage-activated calcium currents, a transient T-type and a PL-sustained type, have been measured in isolated, cultured white bass horizontal cells. These two voltage-activated calcium currents were found to be modulated by two independent second-messenger systems. Furthermore, activation of either second-messenger system led to similar changes in calcium current activity. Activation of the cyclic AMP second-messenger pathway or the sn-1,2-diacylglycerol (DAG) second-messenger system resulted in a significant decrease in the amplitude of the transient current and a simultaneous large increase in the amplitude of the sustained current. Both second-messenger systems achieved their effects through protein phosphorylation. The cyclic AMP pathway resulted in the activation of protein kinase A (PKA) and the DAG pathway worked to activate protein kinase C (PKC). Two protein kinase inhibitors were analyzed in this study for their ability to inhibit second-messenger activated protein kinase activity and separate the two pathways. The peptide cyclic AMP-dependent protein kinase inhibitor and staurosporine were found to be nonspecific at high concentrations and inhibited both second-messenger pathways. At low concentrations however, staurosporine specifically inhibited only PKC, whereas adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase inhibitor was selective for PKA. Both second-messenger systems were activated by the neuromodulator, dopamine. Thus one agonist can initiate multiple second-messenger systems leading to similar changes in voltage-activated calcium current activity. The modulatory action on calcium currents produced by one second-messenger system added to the modulatory action resulting from activation of the other second-messenger system. The effect is to alter the magnitude of the horizontal cell calcium currents.

Animals↗
PubMedDate not supplied

The phospholipid/arachidonic acid second messenger system: its possible role in physiology and pathophysiology of metabolism.

The phospholipid/arachidonic acid second messenger system is a signaling system by which systemic regulators (hormones) and local mediators (tissue factors) control certain aspects of tissue metabolism. In vivo and in vitro evidence indicates that these effectors activate phospholipolytic enzymes in cellular membranes. The products of these enzymatic reactions (such as inositol phosphates or arachidonic acid metabolites) can serve as second messengers that can potentially influence glucose, lipid and protein metabolism at the cellular level. Alterations in this second messenger system could be involved in metabolic changes associated with some pathologic conditions as well as certain drug treatments, and thus, a better understanding of the system could reveal new possibilities for therapeutic interventions.

Arachidonic Acids↗
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↗
PubMedDate not supplied

The effect of psychotropic drugs on the interaction of protein kinase C with second messenger systems in the rat cerebral cortex.

The paper describes and compares the influences of the antidepressants (imipramine, mianserin, citalopram), electroconvulsive shock, and the neuroleptics (haloperidol, chlorpromazine and spiperone) on the systems of second messengers related to adrenergic receptors in rat cerebral cortex, measured by generation of cyclic AMP and inositol phosphate (IP), and their influence on the effects of activation of protein kinase C (PKC) by its synthetic activator, phorbol ester (TPA). The effect of PKC-stimulation was expressed as a reduction of noradrenaline-stimulated IP accumulation and, on the other hand, as an enhancement of cyclic AMP response under stimulation with noradrenaline and isoproterenol. When administered chronically, the described antidepressants (unlike the neuroleptics) augmented IP accumulation or left it unchanged, but they reduced PKC's negative feedback with the alpha 1-adrenoceptor. PKC-induced potentiation of cyclic AMP's response to beta-adrenergic receptor stimulation was unchanged or enhanced, while the antidepressants reduced the generation of this second messenger. However, citalopram increased cyclic AMP generation and reduced PKC potentiation. Taking into account the role of PKC in adrenergic receptors cross-talk explains why, despite antagonization of alpha 1-adrenoceptors and induction of beta down-regulation by some antidepressants, enhancement of the process of noradrenergic neurotransmission can occur as a final effect of the action of these drugs. It was found that the action of antidepressants is largely related to the adrenergic system, even when their action on this system is not direct and is accomplished by their influence on another neurotransmitting system, e.g. the serotonergic system.

Animals↗
PubMedDate not supplied

[Theoretical examination of kinetic regularities in interaction of second messenger systems upon activation of cells by an external chemical signal].

A model of cell activation under the action of an external chemical signal is examined. The model is based on the assumption of simultaneous stimulation of, as a minimum, two different systems of second messengers interacting with each other. The kinetics of intracellular response may be principally different in character depending on the relation of model parameters. Ligand specificity manifests itself either in qualitative changes in the behavior of the system under the action of different ligands of the same class or in changes in the efficiency of intracellular response. In terms of these notions an interpretation of experimental data on cytoplasmic Ca2+ concentration oscillations in individual cells is presented. Methods for experimental verification of the model are considered.

Calcium↗
PubMed1993

UTP activates multiple second messenger systems in cultured rat astrocytes.

In astrocytes, a number of second messenger systems are activated upon stimulation with ATP. Recently, UTP has been demonstrated to have effects similar to ATP in some cell types. To determine if this was also true in astrocytes, cultured cells were stimulated with UTP which was found to evoke thromboxane release, stimulate inositol phospholipid turnover and increase intracellular free calcium concentration. A 53 kDa protein was identified on astrocyte membranes by immunoblotting with an antibody raised against a putative rat fibroblast P2U receptor. These data indicate that astrocytes possess a UTP-sensitive receptor which may be distinct from the P2Y-purinergic receptor.

Adenosine Triphosphate↗
PubMed1988

Autoradiographic analysis of second-messenger systems in the gerbil brain.

Quantitative in-vitro autoradiographic study was performed to localize two prominent second-messenger systems (the adenylate cyclase and phosphoinositide systems) in the normal gerbil brain. [3H] Forskolin and [3H] phorbol 12, 13-dibutyrate (PDBu) were used to identify the regional distribution of adenylate cyclase and protein kinase C, respectively. The localization of the forskolin binding was not uniform, being particularly concentrated in the striatum, the accumbens nucleus, the olfactory tubercle, the substantia nigra, the CA3 region of the hippocampus and the molecular layer of the cerebellum. On the other hand, the PDBu binding was rather uniform, although the superficial layer of the cerebral neocortices, the strata oriens of the CA1 region of the hippocampus and the molecular layer of the cerebellum showed relatively dense binding. Quantitative autoradiography of the second-messenger systems in the brain is expected to provide important information concerning the role of neurotransmitters in the pathophysiology of various conditions.

Animals↗
PubMed1993

Phosphoinositide second messenger system is enriched in striosomes: immunohistochemical demonstration of inositol 1,4,5-trisphosphate receptors and phospholipase C beta and gamma in primate basal ganglia.

The neurochemical organization of the basal ganglia has been studied extensively with respect to neurotransmitters, neuropeptides, and their receptors. The chemoarchitecture of the striatum has been found particularly striking, because it distinguishes many substances by their relative distributions within the striosome and matrix compartments of the striatum. Very little is yet known about the differential distribution of second messenger systems in the basal ganglia, however, and no information is available about whether the distribution of second messenger systems is related to the prominent neurochemical compartmentalization of the striatum. We have examined the distribution of the phosphoinositide second messenger system in the primate basal ganglia and substantia nigra, as detected with polyclonal antisera against the inositol 1,4,5-trisphosphate receptor (IP3R), and monoclonal antisera against phospholipase C beta (PLC beta) and phospholipase C gamma (PLC gamma). In the striatum, immunostaining for each of the three proteins was present predominantly in medium-sized neuronal perikarya and in the neuropil. Circumscribed zones of enhanced IP3R, PLC beta, and PLC gamma immunoreactivity appeared in a background of generally weaker staining, and these zones corresponded to striosomes as identified by calbinidin D28k and substance P immunostaining in adjacent sections. Thus, the richest representation of the phosphoinositide system in the primate striatum appears to be in striosomes. In the substantia nigra pars compacta, neurons and neuropil were immunopositive, but in the substantia nigra pars reticulata and in each segment of the globus pallidus, immunostaining was mainly confined to the neuropil. Perikaryal PCL gamma immunoreactivity in the absence of detectable PLC beta or IP3R immunolabeling was found in the magnocellular neurons embedded in the medullary layer between the putamen and the globus pallidus. These observations demonstrate that the phosphoinositide second messenger system is selectively enhanced in neuronal subsystems of the basal ganglia, including striosomes, and suggest that signaling by phosphoinositide pathways elicits discrete effects on input-output processing by the basal ganglia.

Animals↗
PubMed1990

Phosphorylation-independent effects of second messenger system modulators on gamma-aminobutyric acidA receptor complex function.

Recent studies investigating the functional significance of gamma-aminobutyric acidA (GABAA) receptor complex phosphorylation have employed membrane-permeant compounds to manipulate second messenger systems. Although these compounds affect GABAA receptor function, the dependence of these effects on phosphorylation has not been established. Here we report that several second messenger system modulations can decrease GABAA receptor function independently of their effects on protein phosphorylation. Brain membrane vesicles were lysed and resealed in the presence of EDTA to chelate internal Mg2+. Under these conditions, phosphorylation of vesicle proteins was almost completely inhibited, as determined by incorporation of 32P into phosphoproteins. In these lysed/resealed vesicles, an inhibition of muscimol-stimulated 36Cl- uptake was observed with the cAMP analogs 8-(4-chlorophenylthio)-cAMP, N6,O2'-dibutyryl-cAMP, and 8-bromo-cAMP, the protein kinase inhibitor H7, and the adenylate cyclase activator forskolin. In both intact and EDTA-treated lysed/resealed microsacs, cAMP analogs and H7 inhibited binding of the GABAA receptor ligand [3H]SR 95531 at concentrations shown to inhibit muscimol-stimulated 36Cl- uptake. Forskolin was observed to inhibit the binding of t-butylbicyclophosphoro-[35S]thionate, a ligand that binds to a site on the chloride channel. These results demonstrate that compounds commonly used to alter second messenger systems affect the receptor sites and function of the GABAA receptor chloride channel by mechanisms that do not involve protein phosphorylation. In light of these findings, results obtained with these compounds should be interpreted with caution.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗