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Results for “Second Messenger Systems”

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PubMedDate not supplied

Muscarinic cholinergic receptors on murine lymphocyte subpopulations. Selective interactions with second messenger response system upon pharmacological stimulation.

In this study the muscarinic cholinergic receptor capacity and affinity in murine lymphocyte sets and subsets and the biochemical responses obtained by the pharmacological stimulation of cholinergic receptors in these cells was determined by means of binding studies. Saturation assays with the specific radioligand for muscarinic cholinergic receptors ([3H]QNB) showed that B lymphocytes lack high affinity muscarinic cholinergic receptors, while the binding on T cells was a specific and saturable process. Lyt 2.2+ cells have a significantly higher number of receptors (Bmax) than L3T4+ cells; but the equilibrium dissociation constant (Kd) values obtained in both subpopulations did not differ significantly from one another, and resembled the Kd value of T lymphocyte populations. The specific receptor stimulation by carbachol caused a different intracellular signal transduction according the tested cell subtypes. The muscarinic cholinergic stimulation result in a significant inhibition of isoproterenol-stimulated adenylate cyclase system in T, L3T4+ and Lyt 2.2+ cells. On the contrary, Lyt 2.2+ cells were only able to respond to carbachol stimulus increasing cGMP levels and inositol phosphate formation while L3T4+ cells were unable to do it. Results show differences in the expression and in the ability of cholinergic receptors in sets and subsets of murine lymphocytes to trigger intracellular second-messenger systems. The differential receptor expression and the second-messenger response systems could be important to study the modulation of cellular immune response by cholinergic stimulation.

Animals↗

PubMed1994

Expressed mu opiate receptor couples to adenylate cyclase and phosphatidyl inositol turnover.

The recently cloned rat mu opiate receptor cDNA has been expressed in COS and Chinese hamster ovary (CHO) cells to examine the coupling of this receptor to G-protein linked second messenger systems and examine possible coupling to multiple second messenger systems. Morphine (1 microM) reduced both forskolin-stimulated cAMP levels and IP3 levels by 20 +/- 5 and 34 +/- 8% respectively in COS and CHO cell cultures expressing the cloned rat mu receptor cDNA. Both effects could be blocked by naloxone and Gpp(NH)p. These results represent the first clear representation of the second messenger system promiscuity possible with a single cloned opiate receptor.

Adenylyl Cyclases↗

PubMed2001

Alteration of second messengers during acute cerebral ischemia - adenylate cyclase, cyclic AMP-dependent protein kinase, and cyclic AMP response element binding protein.

A variety of neurotransmitters and other chemical substances are released into the extracellular space in the brain in response to acute ischemic stress, and the biological actions of these substances are exclusively mediated by receptor-linked second messenger systems. One of the well-known second messenger systems is adenylate cyclase, which catalyzes the generation of cyclic AMP, triggering the activation of cyclic AMP-dependent protein kinase (PKA). PKA controls a number of cellular functions by phosphorylating many substrates, including an important DNA-binding transcription factor, cyclic AMP response element binding protein (CREB). CREB has recently been shown to play an important role in many physiological and pathological conditions, including synaptic plasticity and neuroprotection against various insults, and to constitute a convergence point for many signaling cascades. The autoradiographic method developed in our laboratory enables us to simultaneously quantify alterations of the second messenger system and local cerebral blood flow (lCBF). Adenylate cyclase is diffusely activated in the initial phase of acute ischemia (< or = 30 min), and its activity gradually decreases in the late phase of ischemia (2-6 h). The areas of reduced adenylate cyclase activity strictly coincide with infarct areas, which later become visible. The binding activity of PKA to cyclic AMP, which reflects the functional integrity of the enzyme, is rapidly suppressed during the initial phase of ischemia in the ischemic core, especially in vulnerable regions, such as the CA1 of the hippocampus, and it continues to decline. By contrast, PKA binding activity remains enhanced in the peri-ischemia area. These changes occur in a clearly lCBF-dependent manner. CREB phosphorylation at a serine residue, Ser(133), which suggests the activation of CREB-mediated transcription of genes containing a CRE motif in the nuclei, remains enhanced in the peri-ischemia area, which is spared of infarct damage. On the other hand, CREB phosphorylation at Ser133 rapidly diminishes in the ischemic core before the histological damage becomes manifest. The Ca2+ influx during membrane depolarization contributes to CREB phosphorylation in the initial phase of post-ischemic recirculation, while PKA activation and other signaling elements seem to be responsible in the later phase. These findings suggest that derangement of cyclic AMP-related intracellular signal transduction closely parallels ischemic neuronal damage and that persistent enhancement of this signaling pathway is important for neuronal survival in acute cerebral ischemia.

Acute Disease↗

PubMed1993

Actions of lithium on the cyclic AMP signalling system in various regions of the brain--possible relations to its psychotropic actions. A study on the adenylate cyclase in rat cerebral cortex, corpus striatum and hippocampus.

It has been estimated that in most industrialized countries 1 person out of every 1000 in the population is undergoing lithium treatment to stabilize their episodic mood disturbances due to manic-depressive illness. Lithium may stabilize mood swings by altering the action of certain neurotransmitters at the synaptic level in the brain. Recent research suggests that lithium alters neurotransmission by affecting neurotransmitter-coupled second messenger systems. A major second messenger system is the adenylate cyclase, which generates intracellular cAMP from ATP. The adenylate cyclases (type I-IV) are regulated by stimulatory and inhibitory receptors, which either stimulate or inhibit the adenylate cyclase activity. The stimulatory and inhibitory neurotransmitter-receptor signals are transferred to the catalytic unit of the adenylate cyclase by Gs and Gi, respectively. The activated receptor induces GTP stimulation of the heterotrimeric G protein, leading to a dissociation of the protein into the active alpha*GTP and the beta gamma complex. The former stimulates the catalytic unit of adenylate cyclase. The stimulation is terminated by a GTPase located on the alpha subunit that converts GTP to inactive GDP. At present, G proteins are known to play a central role in coupling receptors to effector proteins. In addition to extracellular regulation due to neurotransmitters, some adenylate cyclases (type I, III) are regulated by CaM as a consequence of enhanced intracellular concentrations of free Ca2+. The Ca(2+)-dependent stimulation of adenylate cyclase by CaM is assumed to occur by a direct effect on the catalytic unit. The catalytic units sensitive to Ca(2+)-CaM are also subjected to regulation by stimulatory and inhibitory neurotransmitter stimuli. Magnesium is essential for adenylate cyclase activity, since MgATP2- is the enzyme substrate. Furthermore, one Mg2+ site located on the G protein regulates both the receptor agonist affinity and the dissociation of the G protein during the activation cycle. A second Mg2+ site on the catalytic unit is responsible for Mg2+ regulation of the catalytic activity. The present work aimed at investigating the mechanisms by which lithium in vitro and after chronic treatment (ex vivo) affects adenylate cyclase activities in various regions of the rat brain. Lithium in vitro and ex vivo inhibited the selective stimulation of adenylate cyclase by Ca(2+)-CaM in the cerebral cortex. Furthermore, lithium in vitro interacted directly with the catalytic unit of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗

PubMed1998

Stimulation of prohormone convertase-1 mRNA expression by second messenger signaling systems.

The purpose of this study was to investigate the effects of activation of various second messenger signaling systems on gene expression (i.e. mRNA levels) of a peptide hormone processing enzyme called prohormone convertase-1 (PC-1, also called PC-3) in a human pancreatic carcinoid cell line (BON) that expresses several endocrine peptides (chromogranin A, pancreastatin, neurotensin). Pharmacologic activation of adenylate cyclase-cAMP, protein kinase-C and Ca2+ mobilization pathways increased PC-1 mRNA levels and neurotensin secretion. Elevations in PC-1 mRNA levels were dose and time-related. Secretagogue-induced cellular depletion of neurotensin was followed by a replenishment of cellular neurotensin stores and an upregulation of PC-1 mRNA levels. Together, these data indicate that PC-1 mRNA expression is increased with peptide secretion and coordinated with maintenance of cellular stores of peptides.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1991

Hepatocanalicular organic-anion transport is regulated by protein kinase C.

In order to investigate the regulation of canalicular organic-anion transport, we used a hepatocyte transport assay in which canalicular secretion of a model organic anion, dinitrophenyl-glutathione (GS-DNP), was measured in the presence of stimulators and inhibitors of the Ca2+/protein kinase C (PKC) second-messenger system and of the cyclic AMP (cAMP) second-messenger system. Vasopressin (24 nM) and the phorbol ester phorbol 12-myristate 13-acetate (1 microgram/ml), both stimulators of PKC, stimulated GS-DNP efflux by 65 +/- 36% and 55 +/- 28% respectively, whereas staurosporine (10 microM), an inhibitor of PKC, inhibited efflux by 53 +/- 13%. Glucagon and forskolin, both stimulators of the cAMP second-messenger system, as well as the cAMP analogue dibutyryl cAMP and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, did not significantly influence the GS-DNP efflux. It can be concluded that canalicular organic-anion transport in hepatocytes is either directly or indirectly regulated by PKC.

1-Methyl-3-isobutylxanthine↗

PubMed1992

The role of adenylate cyclase in neuropsychiatric disease.

Over the past decade the study of neuropsychiatric diseases has focused on investigating the integrity of various neurotransmitter and second messenger systems. The most extensively studied second messenger system in both human and rodent tissues has been the adenylate cyclase complex. The search for alterations of adenylate cyclase activity in diseased human tissues ranging from postmortem human brain to isolated lymphocytes has been both fruitful and controversial. Discrepancies are apparent between studies investigating alterations in this system in the human brain and peripheral tissues. Animal studies have proved invaluable for the elucidation of the role of the various components of the adenylate cyclase complex (such as the G proteins) in central neurones. Such studies have also contributed to the elucidation of the effects of psychotropic agents on this system. Clearly, alterations in the functioning of the adenylate cyclase complex have been identified in most neuropsychiatric disorders. The significance of such findings in the study of neuropsychiatric disease will be discussed and also the validity of the various tissue systems used in these studies.

Adenylyl Cyclases↗

PubMed1993

Multiple second-messenger pathways mediate agonist regulation of muscarinic receptor mRNA expression.

Muscarinic acetylcholine receptors in the embryonic chicken heart undergo agonist-induced internalization followed by decreases in both receptor number and mRNA expression. Muscarinic agonists cause both inhibition of adenylyl cyclase and activation of phospholipase C in chick heart cells. Treatment of cells with islet activating protein, which blocks coupling of muscarinic receptors to adenylyl cyclase but not phospholipase C, blocks muscarinic receptor-mediated regulation of receptor mRNA levels. Incubation of cells with the partial agonist pilocarpine, which causes inhibition of adenylyl cyclase but not stimulation of phospholipase C, induces less down-regulation of receptor mRNA levels than agonist which regulate both second-messenger systems. Thus, both second-messenger pathways are required for maximal regulation of muscarinic receptor mRNA levels in response to receptor activation. We also demonstrate that the regulation of receptor mRNA by agonist plays an important role in modulating the rate of recovery of muscarinic acetylcholine receptor number following agonist-induced down-regulation.

Adenylate Cyclase Toxin↗

PubMed1986

[Modulation of calcium conductance of the somatic membrane of sensory neurons of the rat upon activation of the adenylate cyclase system].

Intracellular second messenger system modifies the function of the voltage-dependent calcium conductance. Changes in the latter were investigated under the influence of cholera toxin (potent activator of adenylate cyclase). It was found that lower concentrations of toxin led to an increase of calcium conductance, while higher concentrations suppressed it. The bell-shaped dependence between calcium conductance and cholera toxin concentration indicates that cAMP-dependent protein kinase is connected with the intracellular cAMP concentration in the same way, i.e. a rise of the cAMP concentration from the basal level first activates protein kinase and then results in the inhibitory effect due to the cAMP excess.

Adenylyl Cyclases↗

PubMed2005

Molecular mechanisms of hormonal activity. I. Receptors. Neuromediators. Systems with second messengers.

Hormone signal transfer along all of the cell compartments including nucleus is powered by signal transduction systems. Characteristics and importance of hormone receptors, principal components, functional mechanisms, and biological role of different systems with second messengers are described. Considerable examples of the importance of these systems for medicine are adduced. The drugs modifying these systems comprise more than 65% of contemporary medicines.

Animals↗

PubMed1993

Distribution of cAMP in secondary follicles and its expression in B cell apoptosis and CD40-mediated survival.

Apoptosis occurs at a high rate among B cells in germinal centres (GCs). Isolated GC B cells undergo apoptosis spontaneously when cultured in vitro: such self-destruction can be arrested by protein kinase C-activating phorbol esters and by ligating surface CD40. This study sought to explore whether the cAMP-dependent second messenger system played a role in the regulation of GC cell apoptosis and in ligand-promoted survival. First, the distribution of cAMP in GCs was analysed by immunofluorescence staining and confocal laser scanning microscopy in situ: cytoplasmic cAMP was expressed by all cells but was most abundant in the constitutive cells of the light zones, where GC B cell apoptosis and rescue occur. Isolated GC B cells were found to express higher levels of cAMP than quiescent B lymphocytes as assessed both by a competitive binding assay and a newly developed flow cytometric method. Culturing GC B cells alone increased cAMP level, while those cells rescued with the phorbol ester phorbol myristate acetate (PMA) and anti-CD40 exhibited decreased cAMP levels. Resting B lymphocytes showed no change in cAMP level following culture alone, but a significant increase in cAMP levels when co-cultured with PMA and anti-CD40. These data suggest that given identical signals, resting B cells and GC B cells exhibit differential regulation of the cAMP-dependent second messenger system; moreover, this second messenger system appears to be involved in the regulation of apoptosis in GC B cells.

Antigens, CD↗

PubMed1989

Peptide hormones, cytosolic calcium and renal epithelial response.

We have reviewed the evidence that a number of hormones interact with renal tubular epithelial cells. The evidence suggests that in the mammalian renal tubule bradykinin and parathyroid hormone interact with cell surface receptors to initiate the hydrolysis of PIP2 leading to the formation of I 1,4,5P3 and diacylglycerol in the distal and proximal tubule, respectively. The activation of this second messenger system leads to the mobilization of Ca2+ from intracellular stores. Vasopressin does not activate this second messenger system in mammalian renal epithelial cells, and we cannot demonstrate I 1,4,5P3 formation and Ca2+ mobilization either in the rabbit papillary collecting tubules or in MDCK cells. There is evidence emerging, but not discussed here, that angiotensin II may also mediate some of its effects on the mammalian proximal tubule via the inositol polyphosphate second messenger system.

Animals↗

PubMed2002

Effect of panangin on activity of messengers systems in hypertrophied rat myocardium.

The balance between the two major second messenger systems in hypertrophied myocardium was studied in rats receiving panangin for 16 days. Panangin producing stimulating and polarizing effects on cardiomyocyte membrane improved electrophysiological characteristics of hypertrophied myocardium (electrical stability, duration of supernormal excitability period, and action potential), activated the phosphoinositide exchange, and inhibited the adenylate cyclase system. The panangin-induced change in membrane potentials was accompanied by a pronounced inositol response, i.e. a decrease in the content of membrane polyphosphoinositides (phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-biphosphate) in the brain. It was concluded that function of ion channels depends on activity of phosphoinositide- and adenylate cyclase second messengers systems.

Animals↗

PubMed2001

Abnormalities in the cAMP signaling pathway in post-mortem brain tissue from the Stanley Neuropathology Consortium.

There is an established relationship between the monoaminergic neurotransmitter system and mood disorders. In an attempt to define further the pathophysiology of mood disorders, research is focussing on intracellular second messenger systems, including cyclic adenosine 3',5'-monophosphate (cAMP) and the polyphosphoinositol generated second messengers. The availability of tissue from the Stanley Foundation Neuropathology Consortium has offered us the opportunity to make a number of observations with respect to these second messenger systems in tissue from patients with major depressive disorder and bipolar affective disorder. There is evidence that antidepressants stimulate components of the cAMP pathway in patients with depression while mood stabilizers blunt the same pathway in patients with bipolar disorder. Furthermore, downstream targets of this pathway appear to be altered in patients with mood disorders. The relations between changes in second messenger systems, gene transcription, and clinical effects of current therapeutic regimens has implications for development of novel treatments of mood disorders.

Adenylyl Cyclases↗

PubMed1987

Evidence that muscarinic cholinergic receptors selectively interact with either the cyclic AMP or the inositol phosphate second-messenger response systems.

The relative capacities of muscarinic cholinergic receptor (MR) and bradykinin (BK)-receptor activation to increase phosphoinositide hydrolysis and to increase cytosolic Ca2+ were compared in NG108-15 neuroblastoma x glioma and 1321N1 human astrocytoma cells. In 1321N1 cells, the muscarinic cholinergic agonist carbachol and BK each stimulated a concentration-dependent accumulation of inositol phosphates (K0.5 approximately 10 microM and approximately 10 nM respectively) and a rapid increase in cytosolic Ca2+ as determined by quin2 fluorescence. In NG108-15 cells, BK alone stimulated a pertussis-toxin-insensitive accumulation of inositol phosphates (K0.5 approximately 10 nM) under conditions in which pertussis toxin completely inhibited MR-mediated inhibition of adenylate cyclase. BK also stimulated a rapid increase in cytosolic Ca2+ in NG108-15 cells. In contrast, no MR-mediated increase in phosphoinositide hydrolysis or change in cytosolic Ca2+ concentration was observed in NG108-15 cells. These results support the idea that MR selectively interact with either the cyclic AMP or the inositol phosphate second-messenger systems.

Adenylate Cyclase Toxin↗

PubMed1993

Receptor-mediated release of inositol phosphates in the cochlear and vestibular sensory epithelia of the rat.

Various neurotransmitters, hormones and other modulators involved in intercellular communication exert their biological action at receptors coupled to phospholipase C (PLC). This enzyme catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2) to inositol 1,4,5-trisphosphate (InsP3) and 1,2-diacylglycerol (DG) which act as second messengers. In the organ of Corti of the guinea pig, the InsP3 second messenger system is linked to muscarinic cholinergic and P2y purinergic receptors. However, nothing is known about the InsP3 second messenger system in the vestibule. In this study, the receptor-mediated release of inositol phosphates (InsPs) in the vestibular sensory epithelia was compared to that in the cochlear sensory epithelia of Fischer-344 rats. After preincubation of the isolated intact tissues with myo-[3H]inositol, stimulation with the cholinergic agonist carbamylcholine or the P2 purinergic agonist ATP-gamma-S resulted in a concentration-dependent increase in the formation of [3H]InsPs in both epithelia. Similarly, the muscarinic cholinergic agonist muscarine enhanced InsPs release in both organs, while the nicotinic cholinergic agonist dimethylphenylpiperadinium (DMPP) was ineffective. The muscarinic cholinergic antagonist atropine completely suppressed the InsPs release induced by carbamylcholine, while the nicotinic cholinergic antagonist mecamylamine was ineffective. Potassium depolarization did not alter unstimulated or carbamylcholine-stimulated release of InsPs in either organ. In both tissues, the P2 purinergic agonist alpha,beta-methylene ATP also increased InsPs release, but the P1 purinergic agonist adenosine did not. These results extend our previous observations in the organ of Corti of the guinea pig to the rat and suggest a similar control of the InsP3 second messenger system in the vestibular sensory epithelia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1989

Excitatory amino acids: the involvement of second messengers in the signal transduction process.

1. Excitatory amino acids (EAA) can activate second messenger systems in addition to a direct gating of ion channels. A discrete coupling between novel EAA receptor subtypes and second messenger systems has been previously proposed. 2. EAAs have been suggested to activate both adenylate and guanylate cyclases and also to induce phosphoinositide (PI) turnover. The increased PI turnover was observed in both central neurons and glia, and a "quisqualate-type" receptor has been most frequently involved, which may differ from the quisqualate receptor previously defined by electrophysiological studies. 3. The roles of EAA-induced calcium influx into neurons and raised intracellular calcium levels are discussed regarding the activation of phosphoinositide turnover. 4. This review examines the data supporting a link between EAA receptors and second messengers and considers whether there is any need for adopting new EAA receptor subtypes. Also, the use of the Xenopus laevis oocyte for expressing EAA receptors and studying any putative links to second messenger systems is discussed.

Adenylyl Cyclases↗

PubMed1992

Regulatory pathways governing modulation of fungal gene expression by a virulence-attenuating mycovirus.

A viral double-stranded RNA associated with virulence attenuation (hypovirulence) in the chestnut blight fungus (Cryphonectria parasitica) has been shown by DNA-mediated transformation to be responsible for transmissible hypovirulence. In addition to reduced virulence, the fungal strain harboring this virus exhibits a diverse array of characteristics, termed hypovirulence-associated traits, which distinguish it from an isogenic virus-free strain. We have investigated one of these traits, suppressed lac-1 (laccase) transcript accumulation. Two different and opposing regulatory pathways appear to govern lac-1 transcript levels in the virus-free strain: a stimulatory pathway was found to be dependent on the inositol trisphosphate (IP3) and calcium second messenger systems. A second pathway limiting transcript accumulation was shown to require ongoing protein synthesis. Additionally, changes in the level of lac-1 transcript accumulation were found to be related to modulation of promoter activity and this activity was shown to be suppressed in the virus-containing strain. We conclude that this hypovirulence-associated virus interferes with transduction of an IP3-calcium-dependent signal that is required for stimulation of lac-1 transcription. The perturbation of such signal transduction pathways by hypovirulence-associated viruses may account for the manifold symptoms associated with transmissible hypovirulence.

Ascomycota↗