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At least 649 records · Page 36Linked to original sources
PubMed1989

Adrenergic receptors mediate changes in c-fos mRNA levels in brain.

Recent evidence supports a role for transient c-fos expression as one step in signalling pathways by which membrane receptor-ligand interactions are transduced into appropriate intracellular responses. The activity of adrenergic receptors is mediated by second messenger systems which include ion fluxes, changes in cAMP concentration and enhanced phosphoinositide turnover. In order to determine if C-fos induction was also a step in adrenergic signal transduction in the brain, we performed in vivo studies with drugs specific for different adrenergic receptor types. Unexpectedly, we found that the stress associated with a single intraperitoneal (i.p.) injection of drug vehicle produced a transient increase (averaging 4.0-fold) in c-fos mRNA levels in rat brain. Injection of the alpha 2-adrenoreceptor antagonist, yohimbine, produced a transient increase which was larger in magnitude (averaging 9.6-fold) and longer in duration than that produced by injection of the drug vehicle alone. In experiments designed to ask whether either of these inductions was mediated by specific types of adrenergic receptors, we found that the alpha 2- and beta-adrenoreceptors were involved in both responses, while the alpha 1-receptor played a role in mediating the yohimbine induction, but no detectable role in the solvent induction. One hypothesis consistent with our results is that the norepinephrine (NE) released due to the stress associated with an i.p. injection interacts with postsynaptic beta-adrenergic receptors, resulting in the observed c-fos mRNA induction. When the negative feedback effect of NE, mediated by presynaptic alpha 2-receptors, is blocked by yohimbine, the postsynaptic response is enhanced and prolonged.

Adrenergic alpha-Antagonists↗
PubMed1993

Transcriptional and posttranscriptional regulation of inhibin alpha-subunit gene expression in rat Sertoli cells by 8-bromo-3',5'-cyclic-adenosine monophosphate.

FSH is a major regulator of inhibin production in the testis. FSH effects on Sertoli cell inhibin production are believed to be mediated, at least in part, via the cAMP second messenger system. Previously, it has been shown that 8-bromo-cAMP (8-Br-cAMP) stimulates inhibin-alpha mRNA levels. This study examines whether the cAMP-induced increase in inhibin-alpha mRNA levels results from increased alpha mRNA synthesis, decreased degradation of mRNA, or both. The effects of cAMP on inhibin-alpha gene transcription were examined using nuclear run-on assays. Furthermore, the ability of 8-Br-cAMP to drive the transcription of chimeric constructs containing a 2.2-kilobase (kb) segment of the 5'-regulatory region of the alpha gene placed upstream of the coding region of the luciferase reporter gene was also examined. Data from nuclear run-on assays demonstrated rapid induction of alpha gene transcription by cAMP within 2 h and maximal 4- to 5-fold increase within 4-8 h in primary Sertoli cells. Transfection of TM.4 and JEG.3 cells with an alpha (2.2 kb):luciferase chimeric construct (containing 2.2 kb of the alpha gene 5'-flanking DNA) revealed rapid time-dependent induction of luciferase activity by 8-Br-cAMP in these cell types. To examine the effects of 8-Br-cAMP on alpha mRNA stability, cells were pretreated with medium or 50 micrograms/ml 8-Br-cAMP for 24 h before addition of 5 microM actinomycin D to arrest new RNA synthesis, and the decay of alpha mRNA transcripts was assessed over 24 h by Northern analysis and nonlinear regression.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

Regulation of tyrosine hydroxylase gene expression during hypoxia: role of Ca2+ and PKC.

Gene expression for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, is regulated by reductions in oxygen tension (hypoxia). Hypoxia-induced regulation of the TH gene is due to the binding of specific transcription factors to specific sites on the 5' flanking region of the gene. The purpose of this study was to identify the second messenger system(s) responsible for regulation of the TH gene during hypoxia. Fura-2 fluorescence imaging of rat pheochromocytoma (PC12) cells, an O2-sensitive cell line, revealed that there is an increase in cytosolic calcium (Ca2+) associated with exposure to hypoxia. Based on the evidence that the transcription factors that bind to the TH promoter during hypoxia can also be induced by elevations in cytosolic Ca2+, the role of Ca2+ in the hypoxic regulation of the TH gene was explored. To assay the effect of hypoxia on TH gene expression, Northern blot analyses of total RNA were performed on PC12 cells exposed to hypoxia in the presence or absence of specific inhibitors. The addition of the L-type calcium channel blockers nifedipine or verapamil caused partial inhibition of the hypoxia-induced increase in TH mRNA. The increase in cytosolic Ca2+ during hypoxia was also only partially inhibited by addition of nifedipine. Importantly, chelation of extracellular Ca2+ completely inhibited the increase in TH mRNA by hypoxia. Pretreatment of PC12 cells with BAPTA/AM, an intracellular Ca2+ chelator, inhibited the hypoxic induction of TH gene expression in a dose-dependent manner. Addition of chelerythrine chloride (CHL), a protein kinase C inhibitor, to the media before exposure to hypoxia also resulted in an inhibition of TH induction by hypoxia. These results suggest that hypoxia regulates TH gene expression by a mechanism that is dependent on influx of calcium from the extracellular stores, partially but not exclusively through the L-type calcium channels. These results further suggest that a member of the PKC family is essential for this regulation.

Alkaloids↗
PubMed1995

gamma-interferon production in atopic dermatitis shows differential modification by phosphodiesterase and prostaglandin inhibition.

Interferon-gamma (IFN-gamma) production by peripheral blood mononuclear leucocytes (MNL) is reduced in atopic dermatitis (AD) patients. This may be related to abnormalities in second messenger systems, and increased prostaglandin E2 (PGE2) release from monocytes. We compared the effects of manipulating the second messenger activity using the phosphodiesterase (PDE) inhibitor Ro 20-1724, dibutyryl cyclic adenosine monophosphate (cAMP), and cyclooxygenase inhibition of PGE2, on IFN-gamma production by cultured MNL from AD patients (n = 9) and normal controls (n = 10). Ficoll-Hypaque-separated MNL were cultured for 48 h with OKT3 stimulation, and cAMP, Ro 20-1724, or indomethacin. Supernatants were analysed for IFN-gamma by ELISA. Basal IFN-gamma was lower in AD patients, and the increase in IFN-gamma production with OKT3 was 6.5-fold greater in control subjects than patients with AD. Culture with indomethacin significantly enhanced OKT3-stimulated IFN-gamma production in both groups, whereas OKT3-stimulated IFN-gamma production was abolished with dibutyryl cAMP. IFN-gamma production was significantly lower with Ro 20-1742 in AD than in normal controls. We have shown reduced IFN-gamma release from unstimulated and stimulated MNL in AD patients compared with normal controls. The addition of indomethacin increased IFN-gamma production in both groups, although the increase was less in AD patients, suggesting an intrinsic cellular defect. IFN-gamma release from AD MNL was more sensitive to the inhibitory effects of PDE, and this may be due to increased PDE activity, or the hyperdynamic cAMP system present in atopics.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Assessing the role of ortho-substitution on polychlorinated biphenyl binding to transthyretin, a thyroxine transport protein.

ortho-Substituted polychlorinated biphenyls (PCBs) make up a large part of the PCB residue found in the environment and human tissues. Our laboratory as well as others have demonstrated that ortho-substituted congeners exhibit important biological activities by aryl hydrocarbon (Ah) receptor-independent mechanisms, including changes in second messenger systems necessary for normal cell function and growth. Previous structure-activity relationship (SAR) studies on second messengers and transthyretin (TTR; prealbumin) binding focused little attention on the ortho-substituted PCBs. Disruption of thyroid hormone (TH) transport is one potentially important mechanism by which PCBs can alter TH homeostasis. A more systematic study of PCB binding to TTR, a major TH transport protein, was undertaken, in which the role of ortho-substitution was more thoroughly investigated. Results from this study indicated that the ortho-only substituted series showed significant binding activity and the relative affinities were 2,2',6 > 2,2' = 2,6 >> 2 = 2,2',6, 6'. As anticipated on the basis of steric considerations, bromine was shown to be more active as an ortho-substituent where the relative affinity of 2,2'-Br was equivalent to 2,2',6-Cl. The congener patterns (di-meta-substitution in one or both rings) most closely resembling the diiodophenolic ring of thyroxine (T(4)) showed the highest binding activity. Multiple ortho-substituents were shown to decrease binding activity in such patterns. Congener patterns (single meta-substitution in one or both rings) more closely resembling the monoiodophenolic ring of T(3) showed significantly lower binding activity, consistent with the relatively low binding activity of T(3) and smaller size of chlorine compared to iodine. The addition of ortho-substitution to such patterns gave variable results depending on the substituent relationship (adjacency or nonadjacency) to the pattern. Some patterns such as 2, 2',4,4',5,5' showed good binding activity and represent common congeners in the commercial Aroclor mixtures and in the environment. The binding potencies of ortho-PCBs to TTR may represent a signature SAR that predicts specific biologic/toxic effects. In this regard, the binding potencies were consistent with measured biological activities of these PCBs, including effects on cell dopamine content, Ca(2+) homeostasis, and protein kinase C translocation in neuronal cells and brain homogenate preparations.

Aroclors↗
PubMed2005

Luteinizing hormone-releasing hormone agonist effects on skeletal muscle: how hormonal therapy in prostate cancer affects muscular strength.

PURPOSE: Since the discovery of Huggins in 1941 demonstrating the androgen dependence of prostate cancer cells, the use of pharmacological therapies to decrease systemic androgen concentrations has been one of the main treatment options for prostate cancer. Despite their efficacy luteinizing hormone releasing hormone agonists (LHRHas) have a number of side effects, of which many have not been fully investigated in humans. This review focuses on the effects of LHRHas on skeletal muscle in 3 main areas, namely effects at the androgen receptor, at the neuromuscular junction and on skeletal muscle myofibers. Since prostate cancer is predominantly a disease of elderly individuals, the aging effects of LHRHa therapy on skeletal muscle are magnified and of clinical importance. MATERIALS AND METHODS: A comprehensive MEDLINE search was performed of pertinent studies in the literature relating to the use of LHRHa and skeletal muscle. RESULTS: LHRHas affect 3 primary sites within the skeletal muscle system, namely androgen receptor, the neuromuscular junction and second messenger systems, including insulin-like growth factor-1. All sites have been demonstrated to lead to a decrease in isokinetic exercise strength in large muscle groups. CONCLUSIONS: The musculoskeletal effects of LHRHas for the treatment of prostate cancer should be counteracted via a program of exercise strength training to decrease the morbidity associated with skeletal muscle weakness.

Aged↗
PubMed2004

Salutary properties of YC-1 in the cardiovascular and hematological systems.

The soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) second messenger system provides a complex and highly regulated mechanism for signal transduction events and ensuing functional responses through a cascade of serine/threonine protein kinase-dependent pathways. Nitric oxide (NO) and carbon monoxide (CO), two unique diatomic gases endogenously produced by the respective enzymes nitric oxide synthase (NOS) and heme oxygenase (HO), stimulate cellular sGC and synthesize cGMP within the vasculature. Emerging evidence suggests that the independent NOS and HO systems provide reciprocal and complimentary approaches that act to regulate cardiovascular and hematological homeostasis as well as provide protection to the vasculature in response to inimical stimuli or following the onset of vasoproliferative disease. Recent results from our laboratory and others suggest that the newly identified, chemically synthesized benzyl indazole derivative YC-1 is capable of exerting multifunctional and broad-ranging effects in the cardiovascular and hematological systems. YC-1 has been demonstrated to possess redundant biochemical mechanisms that confer significant stimulation upon NO- and CO-regulated, cyclase-dependent events. Ultimately, these acute molecular processes eventuate in YC-1-dependent modulation of platelet and vascular smooth muscle cell (SMC) and endothelial cell (EC) function under both eutrophic and deleterious conditions. Based on accumulating evidence, YC-1 has been suggested to serve as a potential therapeutic adjuvant to be used in interventional medicine, and these results may indicate the existence of an endogenous " YC-1-like" compound that would be the focus of much anticipated investigation. The purpose of this review, therefore, is to provide update information on the mechanisms and physiologic and pathophysiologic roles of the pivotal new multifunctional agent YC-1 in the cardiovascular and hematological systems, and to provide evidence for its potential use as a clinically relevant salutary agent.

Animals↗
PubMed1992

Age-related differences in the phosphoinositide system in rat neostriatum.

The phosphoinositide cycle is an important second messenger system that may be involved in the therapeutic action of lithium. Elderly patients taking lithium often experience beneficial effects at lower doses and serum levels than their younger counterparts. To investigate age-related differences in lithium's effects on the phosphoinositide system, neostriatal slices from 3-, 10-, and 24- to 26-month-old Fischer 344 rats were labeled with [3H]-myoinositol and exposed for a 25-minute incubation period to oxotremorine-M and varying lithium chloride concentrations. Inositol phosphatase accumulation was significantly greater in 10- and 24- to 26-month-old than in 3-month-old rats. Further investigations may clarify the underlying mechanisms for such age-related differences.

Aging↗
PubMed1993

Regulation of hippocampal muscarinic receptor function by chronic nerve growth factor treatment in adult rats with fimbrial transections.

Effects of chronic intraventricular administration of recombinant human nerve growth factor on hippocampal muscarinic receptor densities and muscarinic receptor-linked second messenger systems were determined in adult rats 21 days following partial or full unilateral fimbrial transections. First, autoradiographic analysis of muscarinic receptors was carried out using [3H]quinuclidinyl benzilate for total muscarinic receptors, [3H]pirenzepine for M1 receptors and [3H]AF-DX 384 for M2 receptors. Partial fimbrial transections did not significantly alter the density of these muscarinic receptor populations in the dorsal or ventral hippocampus and there was no effect of chronic (1 micrograms every other day, 21 days) recombinant human nerve growth factor treatment. In contrast, in animals receiving full fimbrial transections which by themselves did not alter muscarinic receptor density, recombinant human nerve growth factor treatment increased the density of [3H]quinuclidinyl benzilate binding sites, M1 receptors, and M2 receptors by approximately 40% in the CA1 region. Secondly, we determined the effect of chronic recombinant human nerve growth factor treatment on muscarinic receptor-mediated second messenger production in rats with either partial or full unilateral fimbrial transections. In partially fimbriectomized rats, oxotremorine-induced inositol triphosphate production by hippocampal slices was increased by 81% on the lesioned side of animals treated with a control protein. This lesion-induced supersensitivity of M1 muscarinic receptor function was prevented by chronic recombinant human nerve growth factor treatment. In recombinant human nerve growth factor-treated animals, inositol triphosphate production was similar to values on unlesioned control sides. The muscarinic receptor-mediated increase in cyclic GMP levels was not altered by fimbrial transections or recombinant human nerve growth factor treatment. In animals with full unilateral fimbrial transections, oxotremorine-induced inositol triphosphate production was increased by 99% on the lesioned side of animals treated with a control protein and treatment with recombinant human nerve growth factor did not alter this denervation-induced supersensitivity of muscarinic receptor transduction signal. Chronic recombinant human nerve growth factor treatment did not affect the levels of inositol triphosphate on the contralateral unlesioned side of either partial or full fimbriectomized animals. Earlier studies indicate that chronic nerve growth factor treatment increases the presynaptic function of hippocampal cholinergic neurons surviving partial fimbrial transections. The findings of the present study indicate that these presynaptic effects translate into functional changes at the level of postsynaptic muscarinic receptors in the hippocampus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

The inositol trisphosphate receptor gene family: implications for normal and abnormal brain function.

1. The phosphatidyl inositol (PI) second messenger system has been extensively investigated in the past decade. This complex pathway results in the production of two second messengers, one of which, inositol 1,4,5-trisphosphate, will be the focus of this review. 2. The intracellular receptor for this second messenger (IP3R) has been purified, reconstituted and extensively characterized in both brain and peripheral tissues. 3. Localization and functional studies show that IP3 binding causes the receptor to release portions of the intracellular calcium stores. 4. Multiple modulators of the receptor have been identified, including pH, calcium concentration, adenine nucleotide concentration and phosphorylation. 5. The cDNA for this molecule has been cloned from a number of sources. Studies of the molecular structure of the receptor have revealed additional levels of complexity including multiple alternative splicing events in the initially cloned cerebellar (Type I) receptor, as well as the existence of highly related but distinct cDNAs which likely reflect a gene family. 6. There is suggestive evidence linking the PI system, and thus the IP3R, to bipolar disorder and the actions of lithium.

Animals↗
PubMed1995

Roles of specific metabotropic glutamate receptor subtypes in regulation of hippocampal CA1 pyramidal cell excitability.

1. Metabotropic glutamate receptors (mGluRs) are coupled to various second-messenger systems through guanosine 5'-triphosphate-binding proteins. To date, at least seven mGluRs have been cloned, and these mGluR subtypes can be divided into three major groups on the basis of similarities in amino acid sequence, coupling to second-messenger cascades in expression systems, and pharmacological profiles. These groups include group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), and group III (mGluR4, mGluR6, and mGluR7). 2. On the basis of its selective activation of phosphoinositide hydrolysis in brain slices and its ability to activate mGluR1a expressed in Xenopus oocytes, others have suggested that 3.5-dihydroxyphenylglycine (DHPG) may be selective for group I mGluRs. Consistent with this hypothesis, we report that DHPG also activates mGluR5 expressed in oocytes, whereas it is inactive at mGluR4 and mGluR7 expressed in baby hamster kidney (BHK) cells. The compound (2S,1'R,2'R,3'R)-2-(2.3-dicarboxycyclopropyl)glycine (DCG-IV) activates both mGluR2 and mGluR3 at submicromolar concentrations, whereas it is inactive at mGluR4 and mGluR1, suggesting that this compound may be selective for group II mGluRs. Consistent with this hypothesis, we find that DCG-IV does not activate mGluR5 expressed in oocytes and does not activate mGluR7 expressed in BHK cells. These findings suggest that DHPG and DCG-IV are highly selective agonists for group I and group II mGluRs, respectively. 3. Previous studies that have examined the physiological roles of mGluRs have generally used agonists that do not differentiate between the various subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Mycotoxins reveal connections between plants and animals in apoptosis and ceramide signaling.

Plants undergo programmed cell death during development and disease in contexts that are functionally analogous to apoptosis in animals. Recent studies involving plant cell death induced by mycotoxins, pathogens and lethal mutations along with the cell-autonomous death during development now point to several conserved connections to apoptosis in animals. Morphological markers indicative of apoptosis recently reported in plants include TUNEL positive cells, DNA ladders, Ca2+-activated nucleosomal DNA cleavage, and formation of apoptotic-like bodies that occur in some but not all situations involving ordered cell death. In parallel studies with animal and plant cells treated with sphinganine analog mycotoxins our results indicate that the induction and inhibition of death may be mediated by ceramide-linked signaling systems. The presence and significance of ceramide-linked second messenger systems is well documented in animals but is virtually unknown in plants. Further research will discern the manner in which the important function of programmed cell death is conserved as well as diverged between the two kingdoms.

Journal Article↗
PubMed1996

Inhibition of endothelin- and phorbol ester-stimulated tyrosine kinase activity by corticotrophin in the rat adrenal zona glomerulosa.

1. The experiments described in this study were carried out to investigate the role of tyrosine kinase in the acute adrenal response to peptide hormone stimulation, and to determine whether the activity of this kinase may be subject to regulation by other intracellular signalling mechanisms in the adrenal zona glomerulosa. 2. Previous studies from this laboratory have shown that angiotensin II stimulates tyrosine kinase activity in the rat adrenal cortex. This study has shown, for the first time, that endothelin-1 also stimulates tyrosine kinase activity in this tissue. 3. Using the specific inhibitor of protein kinase C (PKC) activity, Ro 31-8220, we have shown that stimulation of tyrosine kinase activity, in response to endothelin-1, angiotensin II or the phorbol ester phorbol 12-myristate 13-acetate, is at least partly dependent on increased PKC activity. 4. The data presented also provide further evidence of cross-talk between signalling systems in the adrenal cortex. Corticotrophin and its intracellular second messenger, cyclic AMP, significantly attenuate the increment in tyrosine kinase activity seen in response to each of the effectors used. 5. The results of this study provide important new evidence for the regulation of protein kinases by other intracellular second messenger systems.

Adrenocorticotropic Hormone↗
PubMed1991

Signal transduction modulation by lithium: cell culture, cerebral microdialysis and human studies.

Considerable evidence suggests that signal transduction pathways are targets of lithium (Li) action. A number of investigators have reported that Li attenuates both adenylate cyclase (AC) activity and phosphoinositide (PI) turnover in rodents and in humans, thus "dampening" these systems. We have studied selected components of these second-messenger systems in a series of clinical and preclinical investigations. To overcome confounding effects of alterations in mood state, we examined AC activity and G-protein ribosylation in peripheral blood cells from 10 healthy volunteers, prior to and following 14 days of Li administration. Basal and postreceptor [cesium fluoride (CsF) or Gpp(NH)p] stimulated AC activity were unaffected in lymphocytes. In contrast, both basal and stimulated AC activity in platelets were significantly augmented, compatible with an attenuation of Gi function. Ribosylation of platelet Gs by cholera toxin was unchanged, whereas that of Gi by pertussis toxin (PT) was increased. Given that undissociated G protein is the preferred substrate for PT, our results suggest that Li interferes with subunit dissociation and the subsequent activation of Gi. To determine if Li has similar effects on Gi in the central nervous system, we measured extracellular (EC) cyclic adenosine monophosphate (cAMP) in rat brain by in vivo microdialysis, revealing a dose-dependent increase in cAMP by norepinephrine (NE) antagonized by propranolol. Chronic (4-week) Li doubled basal EC cAMP, while decreasing the fractional response to 100 microM NE. Thus, using in vivo microdialysis, we observed the reported reduction in NE-stimulated AC activity, but only as a function of elevated basal cAMP. Increased basal AC activity has been observed following chronic Li in both humans and rat tissues but generally has not been considered relevant. The PI generating system is another proposed major target for Li that we have studied using an in vitro cell culture model of peripheral blood cells. Chronic (6-day) exposure of neutrophil-like HL60 cells to 1 mM LiCl did not affect agonist fMet-Leu-Phe (fMLP) induced PI turnover. In contrast, Li attenuated both agonist and phorbol ester stimulated Na+/H+ exchange, suggesting reduced protein kinase C (PKC) function. Western blot analysis revealed altered levels of PKC in both membrane and cytosolic fractions. The functional consequences of these complex effects on the two major signal transduction pathways and their interactions in the intact living organism remain to be elucidated.

Adult↗
PubMed1993

Met-enkephalin induced escape from dexamethasone immunosuppression.

The present study was undertaken to examine whether and what type of interaction occurs between a synthetic glucocorticoid, dexamethasone (DEX) and an opioid peptide, met-enkephalin (MENK) upon superoxide anion (O2-) release from human polymorphonuclear cells (PMN). MENK (10(-8) M) abolished suppressed O2- release from PMNs treated with 10(-7) M DEX. This was the case in unstimulated but not in PMNs stimulated with PMA. The effect of MENK was mediated through pertussis-toxin (PTX) sensitive G-protein and since it was abolished by H7 probably involves protein kinase C (PKC) as a second messenger system. Thus, MENK can abolish DEX induced suppression of O2- release from human PMNs possibly through the interaction of second messenger pathways.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1996

NMDA-mediated activation of the NO/cGMP pathway: characteristics and regulation in cultured neocortical neurones.

The linkage of the N-methyl-D-aspartate (NMDA) subtype of L-glutamate receptor to the nitric oxide (NO)/3, 5'-cyclic guanosine monophosphate (cGMP) intracellular signalling system was investigated in murine neocortical cultures by examining the effects of NMDA antagonists, NO synthase inhibitors, and drugs targeting second messenger systems on NMDA-stimulated synthesis of cGMP. NMDA-stimulated synthesis of cGMP was time- and concentration-dependent, and inhibited by competitive (LY 274614, 100 mu M) and non-competitive NMDA antagonists (MK-801 30 mu M, 7-chlorokynurenate 100 mu M, and ifenprodil 100 mu M). NO synthase inhibitors (NG-nitro-L-arginine, KN-62, diphenyleneiodonium) and LY 83583, an inhibitor of guanylate cyclase, all inhibited NMDA-stimulated cGMP synthesis in a concentration-dependent manner, demonstrating its dependence on the two enzymes. Phorbol 12-myristyl 13-acetate (0.1 mu M), arachidonic acid (1 mu M), and thapsigargin (10 mu M) produced approximately 50% inhibition of NMDA-induced cGMP synthesis. These observations demonstrate that all domains of the NMDA receptor-complex and of NO synthase are active in neocortical neuronal cultures, and that the essential NO/cGMP signalling system has complex interactions with other second messengers.

Animals↗
PubMed1996

The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain.

The function of the phosphoinositide second messenger system was assessed in occipital, temporal, and frontal cortex obtained postmortem from subjects with bipolar affective disorder and matched controls by measuring the hydrolysis of [3H]phosphatidylinositol ([3H]PI) incubated with membrane preparations and several different stimulatory agents. Phospholipase C activity, measured in the presence of 0.1 mM Ca2+ to stimulate the enzyme, was not different in bipolar and control samples. G proteins coupled to phospholipase C were concentration-dependently activated by guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) and by NaF. GTP gamma S-stimulated [3H]Pl hydrolysis was markedly lower (50%) at all tested concentrations (0.3-10 microM GTP gamma S) in occipital cortical membranes from bipolar compared with control subjects. Responses to GTP gamma S in temporal and frontal cortical membranes were similar in bipolars and controls, as were responses to NaF in all three regions. Brain lithium concentrations correlated directly with GTP gamma S-stimulated [3H]Pl hydrolysis in bipolar occipital, but not temporal or frontal, cortex. Carbachol, histamine, trans-1-aminocyclopentyl-1,3-dicarboxylic acid, serotonin, and ATP each activated [3H]Pl hydrolysis above that obtained with GTP gamma S alone, and these responses were similar in bipolars and controls except for deficits in the responses to carbachol and serotonin in the occipital cortex, which were equivalent to the deficit detected with GTP gamma S alone. Thus, among the three cortical regions examined there was a selective impairment in G protein-stimulated [3H]Pl hydrolysis in occipital cortical membranes from bipolar compared with control subjects. These results directly demonstrate decreased activity of the phosphoinositide signal transduction system in specific brain regions in bipolar affective disorder.

Adenosine Triphosphate↗
PubMed2000

Is platelet release of 2-arachidonoyl-glycerol a mediator of cognitive deficits? An endocannabinoid theory of schizophrenia and arousal.

The discovery of blood platelet's ability to release 2-arachidonoyl-glycerol (2-AG), a highly lipophilic cannabinoid molecule may usher in a radical change in our understanding of how the vascular system interacts with the brain. This paper primarily extends Kayai's second messenger imbalance theory of schizophrenia, suggesting that 2-AG is the unidentified second messenger system that Kayai theorized was unbalanced in schizophrenia; furthermore, that a chronic over-release of 2-AG by platelets may be a causal factor in the cognitive deficits associated with negative symptom schizophrenia. Finally, platelet release of 2-AG may also be the causal agent in the cognitive deficits associated with states of high arousal, shock and in other conditions that feature heightened platelet activation. As such, heightened platelet activation may be a profoundly important vector for changing endogenous cannabinoid levels in the brain.

Antipsychotic Agents↗