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PubMedDate not supplied

Influence of internal calcium stores on calcium-activated membrane currents in smooth muscle.

Agonist-induced activation of second messenger systems that increase inositol 1,4,5-trisphosphate concentration plays an important role in the mobilisation of stored Ca2+ in smooth muscle. Release of Ca2+ which occurs spontaneously or by agonist stimulation causes activation of Ca(2+)-sensitive currents. Experiments using selective modulators of the Ca2+ uptake and release mechanisms of the sarcoplasmic reticulum provide evidence that depletion of the internal Ca2+ store triggers an influx of Ca2+ from the extracellular space. Recent data suggest that pool depletion causes the opening of non-selective cation channels which are possibly similar to those previously designated 'receptor-operated Ca2+ channels'. Ca2+ entry through these channels not only refills the internal Ca2+ pool, but also modulates membrane excitability by stimulating Ca(2+)-activated currents.

Animals↗
PubMed1993

The neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) increases levels of inositol 1,4,5-trisphosphate in the tentacle retractor muscle of Helix aspersa.

The C3 neurone, which acts as a motoneurone for the tentacle retractor muscle in Helix aspersa, contains both Phe-Met-Arg-Phe-NH2 (FMRFamide) and acetylcholine (ACh). Each of these transmitter substances evokes contraction of the isolated muscle. FMRFamide induces a delayed rise in tension followed by phasic contractions. Unlike the response to ACh, this response is not associated with a depolarization of the muscle cells. Here we show that FMRFamide stimulates the inositol phosphate second messenger system in the muscle and causes a significant increase in total inositol trisphosphate (InsP3) levels. The isomer which releases intracellular Ca2+ stores, inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), is increased in a similar proportion to the total InsP3. The production of Ins(1,4,5)P3 is therefore likely to be involved in the response of the muscle to FMRFamide and may account for the oscillatory nature of the mechanical response. The N-terminally extended heptapeptide pGlu-Asp-Pro-Phe-Leu-Arg-Phe-NH2 (pQDPFLRFamide), which relaxes the muscle, had no acute effect on InsP3 levels. Indirect evidence also indicates that intracellular Ca2+ stores are required for the generation of the FMRFamide response.

Amino Acid Sequence↗
PubMed1992

Galanin receptors and their second messengers in the lumbar dorsal spinal cord.

The ligand binding properties of galanin receptors were examined in crude synaptosomal fraction preparations of lumbar dorsal spinal cord, using chloramin-T mono-iodinated porcine Tyr26 galanin as ligand. The equilibrium binding of [125I]galanin showed the presence of a single population of high-affinity binding sites with KD = 0.6 +/- 0.2 nM in a concentration of 55 +/- 15 fmol mg-1 protein (Bmax). The N-terminal fragments galanin (1-16) and galanin (1-12) fully displaced specific [125I]galanin binding from membranes with IC50 values 6 nM and 4 microM, respectively. The C-terminal fragment galanin (17-29) did not displace [125I]galanin when applied in the concentration range 10(-11)-10(-4) M. GTP inhibited the specific binding of [125I] galanin in a concentration dependent manner, with 54% inhibition at 1 mM, suggesting that the galanin receptor found in lumbar dorsal spinal cord is G-protein coupled. Second messenger systems, through which the galanin receptor in lumbar dorsal spinal cord may exert its effect, were also studied. A galanin (10 microM) produced inhibition (58%) of the depolarization induced cGMP increase was found, whereas galanin (10 microM) did not inhibit the noradrenalin (100 microM) activated cAMP synthesis or phosphoinositide turnover in tissue slices of the spinal cord. Bilateral transection of the sciatic nerve at midthigh level 14 days prior to the binding experiment was performed, a treatment which is known to cause a dramatic increase of galanin-like immunoreactivity in the superficial layers of the dorsal spinal cord, dorsal root ganglion and in galanin mRNA levels, but no significant effect on Bmax or KD of the galanin receptor was found.

Animals↗
PubMed1998

Cerium ions in the histochemical demonstration of second-messenger enzymes.

Second-messenger systems are involved in the regulation of numerous cellular processes. Adenylate cyclase (AC) and guanylate cyclase (GC) enzymes are in key positions in the regulation of these systems. The cerium method has been successfully applied to demonstrate amine- and neuropeptide-stimulated AC in rat nervous and adipose tissues and human sweat glands at the electron microscopic level. AC was also localized in cultured neurons. Nitric oxide compounds stimulated GC were demonstrated in rat hippocampal areas. Enzyme reactions were located in neurons pre- and postsynaptically in synapses; in addition, GC activity was seen intraneuronally and in glial cells. Adipocytes and eccrine glandular cells exhibited reaction products in their plasmalemmas. Optimal histochemical conditions are described, combined with control experiments. Some handicaps, related to the sensitivity of the enzymes to the fixatives, penetration problems of cerium salts, and especially the specificity of the method in phosphatase enzyme histochemistry in general are discussed.

Adenylyl Cyclase Inhibitors↗
PubMedDate not supplied

Developmental expression of intracellular targets of cGMP in rat visual cortex and alteration with dark rearing.

We describe the temporal pattern of mRNA expression of some of the molecular components of the NO/cGMP second messenger system in the developing rat visual cortex and the effect of dark rearing on their expression levels using semiquantitative RT-PCR. mRNA expression for these molecules was altered by dark rearing in one of three ways: (1) no change--rod, olfactory, and cone/testis CNG channels, nonselective cation channels gated by cyclic nucleotides and highly permeable to Ca2+; (2) decrease--cyclic nucleotide phosphodiesterases which regulate cyclic nucleotide levels, and soluble guanylyl cyclase, the key synthetic enzyme producing cGMP and potently activated by nitric oxide; and (3) increase--cGMP kinase 1, a key enzyme activated by cGMP to phosphorylate a variety of intracellular proteins including cytoskeletal elements. These data suggest important and distinct roles for the cGMP system in both early and late developmental events in the rat visual cortex.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Internalization and desensitization of the oxytocin receptor is inhibited by Dynamin and clathrin mutants in human embryonic kidney 293 cells.

Oxytocin (OT) has long been used as an uterotonic during labor management in women, and yet responses to OT infusion remain variable and unpredictable among patients. The investigation of oxytocin receptor (OTR) regulation will benefit labor management, because the clinical practice of continuous iv infusion of OT is not optimal. As with other G protein-coupled receptors, it is likely that the OTR internalizes and/or desensitizes upon continuous agonist exposure. The mechanisms by which this might occur, however, are unclear. Here we explore OTR internalization and desensitization in human embryonic kidney cells by utilizing inhibitors of heterologous second messenger systems and recently available mutant cDNA constructs. We report rapid and extensive internalization and desensitization of the OTR upon agonist exposure. Internalization was unaffected by inhibitors of protein kinase C or Ca(2+) calmodulin-dependant kinase II but was significantly reduced after transfection with dominant-negative mutant cDNAs of G protein-coupled receptor kinase 2, beta-Arrestin2, Dynamin, and Eps15 (a component of clathrin-coated pits). Moreover, desensitization of the OTR, measured by a calcium mobilization assay, was also inhibited by the aforementioned cDNA constructs. Thus, our data demonstrate, for the first time, the importance of the classical clathrin-mediated pathway during agonist-induced OTR internalization and desensitization.

Arrestin↗
PubMed1999

Signal transduction in the rodent pineal organ. From the membrane to the nucleus.

The rodent pineal organ transduces a photoneural input into a hormonal output. This photoneuroendocrine transduction leads to highly elevated levels of the hormone melatonin at night-time which serves as a message for darkness. The melatonin rhythm depends on transcriptional, translational and posttranslational regulation of the arylalkylamine-N-acetyltransferase, the key enzyme of melatonin biosynthesis. These regulatory mechanisms are fundamentally linked to two second messenger systems, namely the cAMP- and the Ca(2+)-signal transduction pathways. Our data gained by molecular biology, immunohistochemistry and single-cell imaging demonstrate a time- and substance-specific activation of these signaling pathways and provide a framework for the understanding of the complex signal transduction cascades in the rodent pineal gland which in concert not only regulate the basic profile but also fine-tune the circadian rhythm in melatonin synthesis.

Animals↗
PubMed1990

Second messengers of insulin action.

Despite significant advances in past years on the chemistry and biology of insulin and its receptor, the molecular events that couple the insulin-receptor interaction to the regulation of cellular metabolism remain uncertain. Progress in this area has been complicated by the pleiotropic nature of the actions of insulin. These most likely involve a complex network of pathways resulting in the coordination of mechanistically distinct cellular effects. Because the well-recognized mechanisms of signal transduction (i.e., cyclic nucleotides, ion channels) appear not to be central to insulin action, investigators have searched for a novel second-messenger system. A low-molecular-weight substance has been identified that mimics certain actions of insulin on metabolic enzymes. This substance has an inositol glycan structure, and is produced by the insulin-sensitive hydrolysis of a glycosylphosphatidylinositol in the plasma membrane. This hydrolysis reaction, which is catalyzed by a specific phospholipase C, also results in the production of a structurally distinct diacylglycerol that may selectively regulate one or more of the protein kinases C. The glycosyl-phosphatidylinositol precursor for the inositol glycan enzyme modulator is structurally analogous to the recently described glycosyl-phosphatidylinositol membrane protein anchor. Preliminary studies suggest that a subset of proteins anchored in this fashion may be released from cells by a similar insulin-sensitive phospholipase-catalyzed reaction. Future efforts will focus on the precise role of the metabolism of glycosyl phosphatidylinositols in insulin action.

Animals↗
PubMed1996

Induction of costimulatory molecules B7-1 and B7-2 in murine B cells. the CBA/N mouse reveals a role for Bruton's tyrosine kinase in CD40-mediated B7 induction.

The binding of CD40 ligand on activated T cells to CD40 on resting B cells induces the expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86). The induction of B7 molecules by CD40 ligand-CD40 interaction represents a critical step in rendering B cells competent for antigen presentation. The CBA/N mouse has a defect in CD40 signalling which has been attributed to a mutation in Bruton's tyrosine kinase. We have compared the ability of murine CD40 ligand to induce B7-1 and B7-2 expression on B cells isolated from CBA/N and wild-type CBA/J mice. We find that the CBA/N defect partially impairs both B7-1 and B7-2 induction via CD40. Subsequent experiments investigated the roles of different second messenger systems in B7-1 and B7-2 induction in normal B cells. In M12 B lymphomas either CD40 cross-linking or cAMP treatment can induce B7 molecules. Here we report that treatment with dibutyryl-cAMP also induces B7 molecules in normal B cells provided that they have been preactivated by CD40 cross-linking. We also find that PMA and ionomycin treatment of B cells induces B7-2 but not B7-1 expression. Our data therefore show roles for BTK, cAMP and PMA/ionomycin in B7 induction, as well as providing further evidence for differential regulation of B7-1 and B7-2 induction in B cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1993

Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor citalopram.

The aim of this study was to evaluate the effect of citalopram, a second generation antidepressant agent producing no beta-down-regulation, on the receptors and second messenger systems related to noradrenergic transmission in the cerebral cortex of the rat. We confirmed that citalopram does not bind to alpha 1-, alpha 2-, and beta 1-adrenoceptors, but we found that it attenuates the inhibitory action of the protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate, on the noradrenergic response from alpha 1-adrenoceptor. In contrast to most antidepressants, chronic treatment with citalopram does not produce beta-down-regulation, but increases the responses to noradrenaline from beta-adrenoceptors without increasing the beta 1-adrenoceptor density. Chronic treatment with citalopram also increases the maximal response from alpha 1-adrenoceptor. The results indicate that beta-down-regulation is not a necessary characteristic of an efficient antidepressant drug.

Adenylyl Cyclases↗
PubMed1990

Second messengers in thrombin-stimulated bone resorption.

Characterized human thrombins and two commercial bovine thrombin preparations were examined for their effects on bone resorption and on the cyclic AMP and phosphoinositide second messenger systems in bone. Human alpha- and gamma-thrombins, as well as both bovine thrombin preparations, stimulated bone resorption in vitro, whereas catalytically inactivated human diisopropylfluorophosphate (DIP)-alpha-thrombin did not significantly stimulate resorption. Human alpha-thrombin and a commercial bovine thrombin preparation increased cyclic AMP production in fetal rat limb bones, but another bovine commercial thrombin preparation and gamma-thrombin did not. Except for DIP-alpha-thrombin, all thrombins increased production of inositol phosphates in fetal rat limb bones at concentrations that stimulated resorption. In time course studies, bovine thrombin increased label in inositol trisphosphate at 30 s, with decreasing effects at later times. Inositol monophosphate increased progressively over 30 min. Our results are consistent with thrombin-stimulated bone resorption being mediated at least partially through the inositol phosphate pathway.

Animals↗
PubMed1991

The role of glycosyl-phosphoinositides in hormone action.

Despite significant advances in the past few years on the chemistry and biology of insulin and its receptor, the molecular events that couple the insulin-receptor interaction to the regulation of cellular metabolism remain uncertain. Progress in this area has been complicated by the pleiotropic nature of insulin's actions. These most likely involve a complex network of pathways resulting in the coordination of mechanistically distinct cellular effects. Since the well-recognized mechanisms of signal transduction (i.e., cyclic nucleotides, ion channels) appear not to be central to insulin action, investigators have searched for a novel second messenger system. A low-molecular-weight substance has been identified that mimics certain actions of insulin on metabolic enzymes. This substance has an inositol glycan structure, and is produced by the insulin-sensitive hydrolysis of a glycosyl-phosphatidylinositol in the plasma membrane. This hydrolysis reaction, which is catalyzed by a specific phospholipase C, also results in the production of a structurally distinct diacylglycerol that may selectively regulate one or more of the protein kinases C. The glycosyl-phosphatidylinositol precursor for the inositol glycan enzyme modulator is structurally analogous to the recently described glycosyl-phosphatidylinositol membrane protein anchor. Preliminary studies suggest that a subset of proteins anchored in this fashion might be released from cells by a similar insulin-sensitive, phospholipase-catalyzed reaction. Future efforts will focus on the precise role of the metabolism of glycosyl-phosphatidylinositols in insulin action.

Animals↗
PubMed1998

Role of cyclic GMP in olfactory transduction and adaptation.

The detection of odor molecules by vertebrate olfactory receptor neurons (ORNs) involves signal transduction mechanisms that are thought to occur primarily through a cyclic adenosine monophosphate (cAMP)-mediated second messenger pathway. There has been intense debate whether cAMP is the sole second messenger responsible for all excitation and adaptation. The recent identification of a distinct form of odor adaptation that depends on the carbon monoxide/cyclic guanosine monophosphate (cGMP) second messenger system demonstrates that cAMP alone cannot account for all phases of adaptation and that multiple second messenger pathways exist in ORNs to perform distinct but closely related olfactory functions.

Animals↗
PubMed1999

Regulation of K+ channel mRNA expression by stimulation of adenosine A2a-receptors in cultured rat microglia.

Previous investigations suggest that the expression of K+ channels in cultured rat microglia is related to the activation status of these cells. Both, lipopolysaccharide (LPS) and agents that raise intracellular cyclic AMP have been shown to inhibit microglial proliferation. LPS also regulates the mRNA expression levels of K+ channels in cultured microglia, which led us to investigate possible regulatory interactions between K+ channels and adenosine A2a-receptors, which are coupled to the cAMP-signal transduction pathway. The selective adenosine A2a-receptor agonist CGS 21680 induced enhanced mRNA expression of both Kv1.3 and ROMK1, as well as an elevation of Kv1.3 protein. The selective adenosine A2a-receptor antagonist aminophenol (ZM 241385) and the nonselective antagonist 8-phenyltheophylline (8-PT) inhibited these effects. Elevations of cyclic AMP by use of dibutyryl cyclic AMP (dbcAMP), phosphodiesterase-inhibitor (RO 20-1724), forskolin, or cholera toxin (CTX), strongly enhanced Kv1.3-mRNA expression, but decreased ROMK1-mRNA levels. Results from experiments with actinomycin D suggest that K+ channel mRNA levels in cultured microglia were regulated by altered mRNA synthesis. Evidently, the CGS 21680-induced effects upon Kv1.3 were mediated via an increase in intracellular cyclic AMP, whereas ROMK1-mRNA expression appeared to be regulated by coupling of adenosine A2a-receptors to an alternative pathway, which involves activation of protein kinase C (PKC). It is concluded that the cyclic AMP second messenger system in microglia is not only involved in regulation of K+ channel activity, but also in regulation of de novo K+ channel synthesis.

Adenosine↗
PubMed1989

Novel recognition site for L-quisqualate sensitizes neurons to depolarization by L-2-amino-4-phosphonobutanoate (L-AP4).

Brief exposure of rat hippocampal slices to L-quisqualate sensitizes pyramidal neurons to depolarization by L-2-amino-4-phosphonobutanoate (L-AP4). We report here experiments designed to clarify the duration, pharmacology, mechanism, and pathway specificity of this 'QUIS-effect'. The quisqualate-induced sensitization to L-AP4 decreases only 3-fold over a 4 h period. No compound besides quisqualate has been found to induce the QUIS-effect, including quisqualate analogues, potent excitatory amino acid agonists, L-glutamate, L-aspartate, and compounds known to stimulate second messenger systems in hippocampal slices. Of 43 compounds assayed here, only 5 are able to block the induction of the QUIS-effect. Although these blockers are also potent ligands at a chloride-dependent glutamate uptake site, the marked difference in rank ordering of compounds for QUIS-effect blockade and uptake site potency suggests that the QUIS-effect is not induced through this uptake site. The QUIS-effect can be induced in the CA1 region, the medial perforant path, and the lateral olfactory tract of the rat, and in the guinea pig CA1. It cannot be induced in the L-AP4-sensitive rat lateral perforant path (LPP), suggesting that the receptors for L-AP4 in the LPP may be distinct from those that are sensitized by quisqualate in the other pathways.

Action Potentials↗
PubMed1992

Second messenger imbalance hypothesis of schizophrenia.

Based on the results of studies on intracellular signaling in platelets of schizophrenics, an imbalance of the second messenger system is proposed: Diacylglycerol (DG), which activates protein kinase C (PKC), was increased, while adenylate cyclase (AC)-cAMP function was decreased. It is proposed that the increased DG/PKC function may entail a decrease in inositol 1,4,5-trisphosphate (IP3)/Ca2+ function and lowering of phosphoinositide turnover. If such a pathological intracellular signaling takes place in the brain, it may cause a distorted balance of protein activation via phosphorylation in neurons, resulting in some of the deficits of schizophrenia. Neuroleptics have been reported to antagonize the above-mentioned pathological processes of intracellular signaling. The imbalance hypothesis of the DG/PKC pathway and AC-cAMP pathway is not inconsistent with the dopamine hypothesis of schizophrenia, because dopamine receptor stimulation is indirectly related to reduction in IP3/Ca2+ function and lowering of phosphoinositide metabolism.

Antipsychotic Agents↗
PubMed1993

Agonist-induced phosphorylation of the luteinizing hormone/chorionic gonadotropin receptor expressed in a stably transfected cell line.

Much of the definitive work on G-protein-coupled receptor phosphorylation and its impact on receptor function has been performed with the catecholamine receptors. Evidence for receptor phosphorylation is lacking, however, for G-protein-coupled receptors that bind larger ligands, such as LH/CG. Using immunoprecipitation techniques and a clonal cell line stably transfected with the LH/CG receptor, we show here for the first time that exposure of cells to hCG induces phosphorylation of its cognate receptor. The hCG-induced increase in receptor phosphorylation requires receptor activation because it cannot be elicited with a hCG antagonist and is mediated at least in part by the cAMP second messenger system. This hypothesis is supported by the finding that the hCG-induced receptor phosphorylation is greatly reduced (but not abolished) in a cell line that overexpresses cAMP phosphodiesterase and that receptor phosphorylation can be induced by activation of endogenous cAMP synthesis with prostaglandin E2 or by addition of 8-bromo-cAMP. Last, we show that LH/CG receptor phosphorylation can be induced with a phorbol ester, but not with a calcium ionophore. We also examined a potential correlation between LH/CG receptor phosphorylation and uncoupling of the receptor from its effector. Although the phorbol ester-induced phosphorylation of the LH/CG receptor can be correlated with uncoupling, other experiments indicate that hCG-induced uncoupling of the LH/CG receptor can occur under conditions where the cAMP-mediated receptor phosphorylation is greatly reduced (or abolished).

Calcimycin↗
PubMed1999

Rapid aldosterone effects on tyrosine phosphorylation in vascular smooth muscle cells.

Non-genomic aldosterone effects are characterized by their rapid onset, their specificity for mineralocorticoids and their insensitivity both to the mineralocorticoid type 1 receptor antagonist spironolactone and to the inhibitors of transcription and translation, cycloheximide and actinomycin D. The aim of the present study was to further characterize the second messenger system involved in the non-genomic pathway of aldosterone with particular emphasis on protein phosphorylation. The rapid increase of free intracellular calcium by aldosterone in VSMC is sensitive to genistein, so that tyrosine kinase activity appears likely to be involved in the signaling pathway. Here, the effect of 100 nmol/l aldosterone (10 min.) on tyrosine protein-phosphorylation was determined in VSMC. Our findings show that aldosterone (100 nmol/l) in combination with shear stress as additional stimulus induces a rapid (within 10 min.) small but consistent increase in tyrosine-phosphorylation compared with aldosterone or shear stress alone. Immunoprecipitation of the MAPK-isoforms ERK 1 and ERK 2 showed an increased phosphorylation after 3 and 5 min.

Aldosterone↗