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PubMed1998

Pharmacologic hemoglobin reversal: the importance of lipid intermediaries and the proposed involvement of the cAMP and phosphatidylinositol second messenger systems.

Humoral and microenvironmental influences have played a major role in recent research into reversing the Hb F to Hb A switch. Early research in this area focused on hormonal influences and showed both thyroid hormone and prolactin could induce small but statistically significant reversals in hemoglobin phenotype. Recent research has focused on the effect of certain lipids in this process. The current study shows a synergy between thyroid hormone and prolactin in inducing a significant switch in adult rat hemoglobin patterns toward the neonatal pattern. Further, it is hypothesized that this synergy is due to the hormones' effect on lipid intermediaries whose effect in turn are proposed to be mediated by the cAMP and phosphatidylinositol second messenger systems.

Animals↗
PubMed1993

Coupling muscle electrical activity to gene expression via a cAMP-dependent second messenger system.

Embryonic-type nicotinic acetylcholine receptor (nAChR) gene expression is regulated by muscle activity. The mechanism by which this activity is transduced to the genome is not known. We have addressed this issue by using a rat primary muscle cell culture system that mimics the in vivo effects of muscle activity on nAChR expression. We report here that the suppression of nAChR gene expression by muscle activity can be reversed by increasing intracellular cAMP levels. This effect is specific to the embryonic-type receptor genes. Electrically insensitive genes such as those encoding the adult-type nAChR epsilon-subunit and creatine kinase are not up-regulated by cAMP. In addition, muscle inactivity caused either by tetrodotoxin or denervation increases cAMP levels and protein kinase A activity, consistent with their proposed role in mediating nAChR gene expression. Finally, we report that this same mechanism appears to regulate other genes, such as those encoding the tetrodotoxin-insensitive sodium channel, MyoD, and myogenin which, like the nAChR, are regulated by muscle electrical activity. Based on these results it is proposed that muscle electrical activity is coupled to gene expression via a cAMP-dependent second messenger system.

Animals↗
PubMed1994

Effects of moxonidine, an imidazoline antihypertensive agent, on second messenger systems in rat brain.

Moxonidine, an imidazoline, binds to alpha 2-adrenoceptors and imidazoline receptors. We sought to determine the effects of moxonidine on accumulation of cAMP, cGMP, and phosphoinositide turnover in minislices of cerebral cortex and brainstem. In cerebral cortex, but not in brainstem, moxonidine inhibited the stimulated production of cAMP, an effect blocked by alpha 2-adrenergic antagonist rauwolscine. It also increased the hydrolysis of phosphoinositide above 100 microM in cerebral cortex and failed to alter accumulation of cGMP in both regions. We conclude that moxonidine is a typical alpha 2-adrenergic agonist inhibiting cAMP production in cerebral cortex, but not in brainstem, its interaction with I1 imidazoline sites in brainstem did not regulate second messenger systems, and moxonidine increased phosphoinositide turnover in cerebral cortex by unknown mechanisms.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1991

Effects of clonidine and other imidazole-receptor binding agents on second messenger systems and calcium influx in bovine adrenal chromaffin cells.

Clonidine and related imidazoline compounds bind to alpha 2-adrenergic as well as to newly described non-adrenergic imidazole/imidazoline receptors in brain and peripheral tissues. The present study was undertaken to identify the signal transduction mechanism coupled to this new class of receptors (imidazole receptors) using bovine adrenal chromaffin cells. Clonidine did not modify the basal or forskolin-stimulated production of cyclic AMP (cAMP), suggesting the absence of functionally active alpha 2-adrenergic receptors in adrenal chromaffin cells. Clonidine also failed to modify the basal and GTP gamma S- or carbachol-stimulated increase in phosphoinositide hydrolysis. However, clonidine increased significantly the production of cyclic GMP (cGMP) as well as the uptake of 45Ca2+. The cGMP response to clonidine was slower (peak at 15 min) and smaller (only about 50% over control) than the response to acetylcholine and was not shared by other agents that bind to imidazole receptors. In contrast, all agents that bind to imidazole receptors increased the influx of 45Ca2+ into chromaffin cells. It is concluded that (a) alpha 2-adrenergic and imidazole receptors are functionally distinct and linked to different signal transduction mechanisms; (b) the classical G-protein coupled soluble second messenger systems are not coupled to imidazole receptors; (c) clonidine may increase cGMP by a non-receptor-mediated intracellular action; and (d) imidazole receptors may regulate intracellular calcium levels through an ion regulating system that may be different from calcium channels.

Adrenal Glands↗
PubMed1990

Cholera and pertussis exotoxins protect mice against the lethal Schwartzman reaction and antagonize the effects of lipopolysaccharide on second messenger systems.

Pertussis toxin, and also cholera toxin are capable of inhibiting the effects of LPS in the elicitation of the generalized Schwartzman reaction. This is a potentially lethal generalized thrombo-haemorrhagic hypersensitivity and inflammatory-type response that occurs after two consecutive injections of LPS. The two exotoxins furnish significant protection against the lethal outcome of this reaction. It is known that the acute haematological and haemodynamic changes are accompanied by alterations in the levels of various endogenous mediators: glucocorticoid hormones, prostaglandins, arachidonic acid metabolites, cytokines and proteases. In vitro effects of LPS on murine leukocyte cell lines can be antagonized by pertussis toxin, implicating a Gi-like regulatory protein in the mediation of these effects. Experiments designed to study the involvement of particular second messenger systems (cAMP and phosphatidylinositol) used by LPS in vivo, revealed that the protective effects conferred by these exotoxins are associated with the antagonization of alterations caused by LPS. No correlation was found between the levels of IL-6 and the mortality rate in this experimental mouse model. The results indicate that G proteins play a role in the generation of the Schwartzman reaction and open a new approach for pharmacological intervention in endotoxemia and in clinical settings with Gram-negative sepsis.

Animals↗
PubMedDate not supplied

Effects of neuropeptide Y on alpha 1-and beta-adrenoceptor-stimulated second messenger systems in rat frontal cortex.

Neuropeptide Y (NPY) (1 microM) significantly reduced the basal cAMP concentration in slices of rat frontal cortex. However, NPY (10(-9)-10(-6)M) did not alter the isoproterenol-stimulated (10(-9)-10(-5) M) accumulation of cAMP in the frontal cortical slices, showing that Y2 NPY receptors do not modulate the beta-adrenoceptor-stimulated adenylase cyclase activity. NPY (10(-8)-2.5 x 10(-5) M) was also demonstrated to stimulate inositol phosphate accumulation in rat frontal cortex slices in a dose-dependent manner. However, NPY (1 microM) did not potentiate the ability of phenylephrine (5 X 10(-8)-10(-4) M), an alpha 1-adrenoceptor agonist, to stimulate inositol phosphate hydrolysis. The combined effects of phenylephrine and NPY (1 microM) on inositol phosphate hydrolysis were additive, suggesting that the alpha 1-adrenoceptor and NPY Y1 receptor sites are located on different postsynaptic sites in rat frontal cortex. This study demonstrates the existence of both Y2 and Y1 NPY receptors in the rat frontal cortex based on second messenger systems, but there does not appear to be an interaction of NPY with either alpha 1- or beta-adrenoceptors.

Animals↗
PubMed1991

Roles of actin filaments and three second-messenger systems in short-term regulation of chick dorsal root ganglion neurite outgrowth.

In a previous study (J. Cell Biol. 109: 1229-1243, 1989), we reported that conditions which increased growth cone calcium levels and induced neurite retraction in cultured chick DRG neurons also resulted in an apparent loss of actin filaments in the growth cone periphery. We further showed that the actin-stabilizing drug phalloidin could block or reverse calcium-ionophore-induced neurite retraction, indicating that the behavioral changes were mediated, at least in part, by changes in actin filament stability. In this study, we have further characterized the calcium sensitivity of growth cone behavior to identify which features of calcium-induced behavioral effects can be attributed to effects on actin filaments alone, and to assess whether two other second-messenger systems, cAMP and protein kinase C, might influence neurite outgrowth by altering calcium levels or actin stability. The results indicated that growth cone behavior was highly sensitive to small changes in calcium concentrations. Neurite outgrowth was only observed in calcium-permeabilized cells when extracellular calcium concentrations were between 200 and 300 nM, and changes as small as 50 nM commonly produced detectable changes in behavior. Furthermore, low doses of cytochalasins mimicked all of the grossly observable features of growth cone responses to elevation of intracellular calcium, including the apparent preferential destruction of lamellipodial actin filaments and sparing of filopodial actin, suggesting that the behavioral effects of calcium elevation could be explained by loss of actin filaments alone. The effects of cAMP elevation and protein kinase C activation on growth cone behavior, ultrastructure, and fura2-AM-measured calcium levels indicated that the effects of cAMP manipulations could be partially explained by a cAMP-induced lowering of growth cone calcium levels and concomitant increased stabilization of actin filaments, but protein kinase C appeared to act through an independent mechanism.

Actins↗
PubMed2003

D-amphetamine-elicited action potential bursts in central snail neurons: role of second messenger systems.

BACKGROUND AND PURPOSE: Neuronal bursts of action potentials are closely related to seizure activity. Amphetamine rarely induces seizures at therapeutic doses, but seizure may occur after the first dose. This study investigated factors affecting d-amphetamine-elicited action potential bursts in isolated central snail neurons. METHODS: The central right parietal neuron 1 (RP1 neuron) from the subesophageal ganglia of the African snail Achatina fulica Ferussac was used to evaluate neurotransmitter systems involved in d-amphetamine-elicited potential burst activity by use of conventional electrophysiological and general pharmacological techniques. RESULTS: d-Amphetamine (135 and 270 microM) elicited bursts of action potentials in the RP1 neuron in a concentration dependent manner. The burst activity was not blocked by pretreatment with prazosin (100 microM), yohimbine (100 microM), propranolol (100 microM), atropine (1 mM), or by continuous perfusion of calcium-free solution. These results suggest that the burst activity elicited by d-amphetamine was not due to activation of the cholinergic or adrenergic receptors of the excitable membrane. The burst firing of action potentials was decreased following extracellular application of the specific protein kinase A inhibitors H89 (N-[2-(p-bromocinnamylamino)-ethyl]-5-isoquinoline sulfonamide, 10 microM), or KT-5720 (10 microM). However, the burst firing of action potentials was not affected after extracellular application of the specific protein kinase C inhibitors Ro 31-8220 (10 microM) or chelerythrine (10 microM). Forskolin (10 microM), an activator of adenylyl cyclase, facilitated the burst firing of action potentials elicited by d-amphetamine. However, in the absence of d-amphetamine, a higher concentration of forskolin (100 microM) was able to elicit burst firing of action potentials. CONCLUSIONS: These results suggest that the action potential bursts elicited by d-amphetamine are associated with the cyclic adenosine monophosphate (cAMP) second messenger system and are not related to the cholinergic or adrenergic receptors or protein kinase C activity in the RP1 snail neuron.

Action Potentials↗
PubMed1992

Effects of isoproterenol and forskolin on carbachol- and fluoroaluminate-induced polyphosphoinositide hydrolysis, inositol trisphosphate production, and contraction in bovine iris sphincter smooth muscle: interaction between cAMP and IP3 second messenger systems.

We have investigated the effects of isoproterenol (ISO) and forskolin on carbachol(CCh)- and fluoroaluminate (AlF4-)-induced phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, myo-inositol 1,4,5-trisphosphate (IP3) production, 1,2-diacylglycerol, measured as phosphatidic acid (PA) formation, and contraction in the bovine iris sphincter smooth muscle. The data from these studies can be summarized as follows. (1) CCh (20 microM) stimulated significantly PIP2 hydrolysis, IP3 production, PA formation, and contraction. (2) Addition of ISO (0.1-25 microM), which raises the tissue cAMP level, to muscle precontracted with CCh attenuated PIP2 hydrolysis, IP3 production, PA formation and contraction in a time- and dose-dependent manner. (3) AlF4- (10 microM) induced a slow but progressive hydrolysis of PIP2, accompanied by parallel production of IP3, formation of PA, and contraction of the smooth muscle. The effects of AlF4- were dose-dependent and inhibited by deferoxamine, an Al3+ ion chelator. (4) Both forskolin (1-25 microM), which directly stimulates adenylate cyclase, and ISO inhibited the responses induced by AlF4- (10 microM) in a dose-dependent manner. (5) NaF (1-5 mM) had no effect on the activity of phospholipase C (PLC), purified from bovine iris sphincter. Furthermore, phosphorylation of the enzyme by catalytic subunit of protein kinase A had no inhibitory effect on PLC activity against PIP2. In conclusion, neither the muscarinic receptor nor PLC are the target sites for cAMP inhibition; instead the putative G-protein, which couples the activated muscarinic receptor to PLC, may be phosphorylated by cAMP-dependent protein kinase. This could attenuate the stimulation of PLC by the G-protein, thus resulting in inhibition of PIP2 hydrolysis and consequently leading to muscle relaxation. These results demonstrate cross-talk between the cAMP and IP3-Ca2+ second messenger systems and suggest that this could constitute a regulatory mechanism for the process of contraction-relaxation in smooth muscle.

Aluminum↗
PubMed1993

Regulation of IgD-receptor expression on murine T cells. II. Upregulation of IgD receptors is obtained after activation of various intracellular second-messenger systems; tyrosine kinase activity is required for the effect of IgD.

The presence of IgD receptors (IgD-R) on T cells during a primary response to antigen causes augmented antibody production and facilitates priming for a secondary response. Cross-linked, but not monomeric IgD leads to a rapid upregulation of these receptors on T cells. As shown in the present study, the rapid upregulation of IgD-specific receptors is also induced by cross-linking of T cell surface molecules known to mediate triggering of T cell activation, such as CD3, CD2, and Thy 1. Furthermore, IgD-R are also upregulated by pharmacologically active compounds that increase intracellular cAMP and by PMA/DiOG plus ionomycin, but not by either PMA or ionomycin alone. The upregulation of IgD-R by anti-CD3 is inhibited by both calphostin C and herbimycin A, while that due to DiOG plus ionomycin is only inhibited by calphostin C. Upregulation of IgD-R by increased cAMP is blocked by HA1004, but not by low concentrations of staurosporine or herbimycin A. IgD itself does not cause an increase in intracellular cAMP, protein kinase C translocation, influx of extracellular Ca2+, or a change in membrane potential. Relatively specific inhibitors of these activation pathways, HA1004, calphostin C, and neomycin, also fail to interfere with IgD-receptor upregulation by IgD itself. However, tyrosine kinase inhibitors, including herbimycin A, tyrphostin C11, and genistein, completely prevent the effect of IgD on IgD-R expression. Although an influx of Ca2+ is apparently not involved, a role for intracellular Ca2+ in the upregulation of IgD-R by IgD on T cells is indicated by the susceptibility to inhibition by BAPTA, W7, and FK520. We conclude that activation of at least three different second-messenger systems can cause IgD-R upregulation, but that the effect of IgD itself requires tyrosine kinase activity, perhaps in an intracellular Ca(2+)-dependent manner.

Animals↗
PubMed1999

Molecular neurobiology for practicing psychiatrists, part 2: how neurotransmitters activate second messenger systems.

Chemical neurotransmission begins when receptor occupancy by a neurotransmitter is converted into an intracellular second messenger that carries the information from the neurotransmitter deep into the target neuron. For clinicians, it is this transfer of neurotransmitter information all the way to the genome that hypothetically explains the therapeutic actions of many psychotropic drugs. This also accounts for why drugs that modify neurotransmission may take time to fully develop their clinical actions.

GTP-Binding Proteins↗
PubMed1989

Second-messenger systems underlying amine and peptide actions on cardiac muscle in the horseshoe crab Limulus polyphemus.

The biochemical mechanisms by which octopamine, catecholamines and the peptide proctolin exert their actions on Limulus cardiac muscle were investigated. Amines produced long-lasting increases in the amplitude of contractions evoked by electrical stimulation. At 10(-5) mol l-1, the apparent order of potency for amine-induced increases in evoked contraction amplitude was dopamine approximately equal to octopamine greater than norepinephrine approximately equal to epinephrine. At this dose, amines produced long-lasting increases in the levels of cyclic AMP (octopamine greater than dopamine approximately equal to norepinephrine approximately equal to epinephrine), but not of cyclic GMP, in Limulus cardiac muscle. Like the amines, the adenylate cyclase activator forskolin enhanced cardiac muscle contractility and increased levels of cyclic AMP, but not of cyclic GMP. The phosphodiesterase inhibitor IBMX produced a transient increase in cardiac muscle contractility, but typically produced long-lasting negative inotropy. This agent increased levels of both cyclic AMP and cyclic GMP in Limulus cardiac muscle. Proctolin and the protein kinase C activator phorbol dB increased the contraction amplitude of the intact heart and the electrically stimulated myocardium. These compounds, as well as dopamine, elicited sustained contractures and rhythmic contractions when applied to deganglionated Limulus cardiac muscle rings. Unlike the amines, proctolin and phorbol dB did not increase cardiac muscle cyclic AMP levels. These results suggest that several second-messenger systems may be utilized by amines and peptides to produce excitatory actions on cardiac muscle fibers of the Limulus heart. Cyclic AMP appears to be an important second messenger underlying the effects of amines to enhance cardiac muscle contractility. Pharmacological data suggest that proctolin may alter cardiac muscle contractility and excitability by a mechanism which involves the phosphatidylinositol pathway. Dopamine, unlike the other amines, produces a number of proctolin-like effects and may activate both the cyclic AMP and the phosphatidylinositol systems in Limulus cardiac muscle.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Second messenger systems as targets for new therapeutic agents: focus on selective phosphodiesterase inhibitors.

Second messengers are intracellular substances whose concentration is regulated by the action on their specific receptors of extracellular regulatory molecules globally known as first messengers. In particular, the cyclic nucleotides cAMP and cGMP help in the coordination of cellular functions, mainly through their stimulatory effect on multisubstrate protein kinases. The pharmacological modulation of cyclic nucleotide levels has been classically attained by acting on the first messenger receptors. However, the possibility exists that an intervention on the enzymes responsible for the synthesis or degradation of such second messengers could yield similar effects. The enzymes involved in the degradation of cAMP and cGMP, the so-called cyclic nucleotide phosphodiesterases (PDEs), are a group of at least 7 enzyme families that share the property of hydrolysing the cyclic nucleotides to their corresponding 5-monophosphate counterparts. At the present time, most of the interest on the potential utility of selective PDE inhibitors is focused on drugs capable of inhibiting PDE IV, one of the cAMP specific phosphodiesterases, because the tissue distribution of PDE IV strongly suggests that pathologies related to the central nervous and immune systems, could be treated in this way. PDE IV inhibitors can be divided into three structural classes: 1) structural analogues of rolipram, 2) structural analogues of nitraquazone and 3) structures related to the xanthine nucleus, such as denbufylline. An overview of the structure-activity relationships for these classes of compounds and a summary of their possible therapeutic potential will be given.

Animals↗
PubMed1993

Immobilization stress induces alterations of second-messenger systems in the gerbil brain.

The effects of immobilization stress on the cerebral second messenger (adenylate cyclase and phosphoinositide) were investigated autoradiographically in mongolian gerbils. After 10 min (10-min stress group, n = 7), or after 6 h (6-h stress group, n = 7) of fixation on a flat board while supine, in vitro autoradiography was performed using [3H]forskolin (3H-FK) and [3H]phorbol-12,13-dibutyrate (3H-PDBu) as specific ligands to identify the distribution of adenylate cyclase and protein kinase C, respectively. In another group of 7 gerbils (control group), the same autoradiographic procedure was performed immediately after the animals were removed from the cage. In the 10-min stress group, FK binding was significantly decreased in the hypothalamus and amygdala, but significantly increased in the basal ganglia including the caudate-putamen and globus pallidus. FK binding in the 6-h stress group tended to increase throughout the brain, rising significantly in the basal ganglia. PDBu binding in either stress group did not change significantly compared to the control group in any region except the hippocampal CA3 region of the 6-h stress group. Under immobilization stress, the adenylate cyclase system may undergo time-dependent and regionally specific changes, while the phosphoinositide system remains relatively stable.

Adenylyl Cyclases↗
PubMed1985

Prostacyclin acts in rat gastric (fundic) mucosa via the intracellular 'second messenger system'.

Using a specific radioimmunoassay technique it seems that Prostacyclin (PG-I2) has a strong effect on the cyclic nucleotide content of the rat gastric (fundic) mucosa. 1 min after an intragastric application of 100 micrograms/kg PG-I2 the cAMP-content and in the 5th min the cGMP-content showed a highly significant decrease. It seems that the basic mechanism of action of PG-I2 is a typical 'hit and run' effect, acting on the intracellular 'second messenger system'.

Animals↗
PubMed1994

Autoradiographic distribution of neurotransmitter and second messenger system receptors in animal brains.

We investigated species difference in binding of major neurotransmitters and intracellular second messengers in the gerbil brain and the rat brain using receptor autoradiography. [3H]Phorbol 12,13-dibutyrate (PDBu), [3H]inositol 1,4,5-trisphosphate (IP3), [3H]PN200-110, [3H]muscimol, [3H]MK-801, [3H]cyclohexyladenosine (CHA),and [3H]quinuclidinyl benzilate (QNB) were used to label protein kinase C, IP3 receptor, L-type calcium channel, gamma-aminobutyric acidA (GABAA) receptor, N-methyl-D-aspartate (NMDA) receptor, adenosine A1 receptor, and muscarinic cholinergic receptor, respectively. Autoradiographic distributions of the bindings of most neurotransmitters and second messengers were particularly found in the limbic system and basal ganglia in both gerbil and rat brains. However, marked differences in these bindings between the gerbil brain and the rat brain were also recognized in the above regions. In particular, among 7 ligands used, the gerbil had high [3H]PDBu and [3H]CHA binding sites throughout the brain compared to those in the rat brain except for a few areas. By contrast, the rat exhibited high [3H]MK-801 binding sites in various brain regions, as compared with the gerbil brain. Thus, the gerbil differ from the rat with respect to the binding sites of major second messengers and neurotransmitters in the brain. The results may help better elucidate the relationship or species difference between gerbils and rats for neuronal function and behavioral pharmacology.

Animals↗
PubMed2003

[Molecular mechanisms of G-proteins coupling with membrane receptors and second messenger systems].

G-proteins transmit the signals from hormone receptors onto intracellular effector systems which take part in production of the second messengers such as cAMP, IP3, DAG and Ca2+. Molecular mechanisms of G-protein participation in the coupling of the seven-domain receptors to adenylate cyclase, phospholipase C and channels for Ca2+ and K+ ions are discussed in this paper. G-protein is a heterotrimers built of alpha-, beta- and gamma-subunits, which dissociate onto alpha- and beta gamma-subunits during interaction with hormone-receptor complex. alpha-subunit as well as beta gamma-dimmer may interact with effector system that leads to acceleration or slowing down of second messengers formation. Molecular mechanisms of such regulatory signal diversification are described. Seven-domain receptors possess very high recognition specificity of G-proteins. It is defined by combination of both alpha- and beta gamma-subunits in the G-protein structure. There is well-defined interaction specificity of G-protein alpha-subunit with effector systems. Combinations of different beta- and gamma-subunits involved in complex formation define interaction specificity of G-protein beta gamma-complex with effector systems. The highest interaction specificity of receptors with G-proteins and G-proteins with effector systems is found during triple complex formations: receptor--G-protein--effector. Such specificity is stronger in living cells than in membrane preparations. It can be an evidence of intracellular factors influence on the processes of interaction of the proteins involved in transmembrane regulatory signal transduction.

Animals↗