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At least 379 records · Page 21Linked to original sources
PubMed1994

Muscarinic receptor-dependent activation of phospholipase C in the developing human fetal central nervous system.

The coupling of muscarinic-cholinergic receptors (mAChR) to adenylate cyclase and phospholipase C (PLC) second messenger systems has been demonstrated in many animal species. However, little is known about this association in the developing human central nervous system. Because of the proposed role of acetylcholine in the regulation of development and differentiation of neural cells, an understanding of these relationships during human fetal development gains importance. We report, in this communication, the coupling of mAChR with PLC in the human fetal brain. This coupling was determined using two independent approaches that relied upon estimating the accumulation of inositol phosphates (IPs) and cytidine diphosphate diacylglycerol (CDP-DAG). Carbachol treatment of brain slices, in the presence of lithium, resulted in the accumulation of IPs. Analysis of the kinetics of this accumulation showed that IP3 and IP2 increased rapidly, reaching a peak or plateau before IP. The results also showed that agonist-stimulated PLC produced two second messengers, IP3 and DAG. The production of DAG was strongly supported by the carbachol-dependent increase of CDP-DAG. The accumulation of IP and CDP-DAG was dependent on agonist concentration. The obtained EC50 values were approximately: carbachol 47 microM; acetylcholine 6 microM; and oxotremorine 25 microM. Unexpectedly, all three agonists demonstrated a similar efficacy. The cholinergic stimulation of inositide hydrolysis appears to be the result of activation of the m1 muscarinic receptor.

Atropine↗
PubMed1990

Atopic dermatitis: a defect of intracellular secondary messenger systems?

The clinical manifestations of atopic dermatitis comprise a complex mixture of pharmacological, physiological and immunological responses. Circumstantial evidence suggests that atopic disease may arise consequent upon the migration of bone marrow-derived cells into the target tissue of skin or respiratory mucosa. Mediator release from such cells has been shown to be abnormal in atopic dermatitis, and itch, the hallmark of the disease, may be the result of chronic inflammatory mediator release into the skin. Abnormal release of mediators has been shown to correlate with inadequate nucleotide control of cell function. In particular, elevated cyclic AMP-specific PDE activity causing cyclic AMP hyporesponsiveness has been found in peripheral blood mononuclear leucocytes in atopic dermatitis. Investigation of this pathway has led to the discovery of additional abnormalities of other secondary messenger systems, including abnormalities of protein kinase C activity and of inositol activation. The biochemical abnormalities may be a consequence of down-regulation of the second messenger systems because of chronic exposure to low levels of inflammatory mediators, but may themselves subsequently permit further mediator release. They may provide a biochemical mechanism for many of the immunological abnormalities seen in atopic dermatitis. In particular, they offer a biochemical explanation for the paradox of increased type 1-mediated immunity and diminished cell-mediated immunity commonly observed in this complex disease.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

MHC class I is functionally associated with antigen receptors in human T and B lymphomas.

We have studied the antibody-induced effect of cross-linking the major histocompatibility complex class I (MHC-I) in human T leukemic cells (Jurkat) and human B lymphoma cells (Solubo, Burkitts lymphoma) on intracellular [Ca2+]i levels. The increase in [Ca2+]i after MHC-I cross-linking in Jurkat cells and Solubo cells was dependent on both intra- and extracellular Ca2+ stores. The initial increase was dependent on intracellular stores but the long-term elevated [Ca2+]i level was due to an influx of Ca2+. The kinetics of Ca2+ release and influx was different in the two cell lines. In both cell lines the increase in [Ca2+]i after MHC-I cross-linking caused upregulation of CD69, an early marker of activation. When studying the effect of MHC-I cross-linking on the TCR- and B cell antigen receptor (BCR)- mediated increase in [Ca2+]i, respectively, we observed that MHC-I had a costimulatory effect on the TCR-mediated increase in [Ca2+]i in Jurkat cells but not on the anti-IgM-mediated activity of Solubo cells. Studies of subpopulations of Jurkat and Solubo cells expressing different levels of MHC-I on their cell surfaces revealed that the TCR- and BCR-mediated increases in [Ca2+]i, respectively, were positively correlated with the level of MHC-I expressed on the cell surface. These observations suggest two different roles in signal transduction for the MHC-I molecules in the T and B cells studied. First, by themselves MHC-I complexes are able to induce activation of intracellular second messenger systems following cross-linking. Second, threshold levels for activation through antigen receptors in T and B cells are dependent on or determined by the actual numbers of MHC-I complexes present in the cell membrane. Thus the present data strongly point to a new, physiological role for MHC-I molecules in T and B cells.

Antigens, CD↗
PubMed1995

Modulation by inositol of cholinergic- and serotonergic-induced seizures in lithium-treated rats.

Hippocampal and cortical EEG recordings in rats were used to monitor the in vivo modulation by lithium of responses to agonists for 5HT2/5HT1c serotonergic (DOI) and cholinergic (pilocarpine) receptors and the influence of inositol administration. Administration of DOI (8 mg/kg) or pilocarpine (30 mg/kg) to rats pretreated with lithium acutely (3 mmol/kg) or chronically (dietary, 4 weeks) resulted in seizures, whereas these doses did not cause seizures without lithium pretreatment. This indicated that lithium most likely affects a signal transduction process common to both systems, which is the phosphoinositide second messenger system. To examine the potential influence of altered inositol levels on these responses, we tested the effects of infusions (10 mg, i.c.v.) of myo-inositol, a precursor of phosphoinositide synthesis, and of epi-inositol, an isomer not used for phosphoinositide synthesis. Administration of myo-inositol (10 mg) slightly reduced the incidence of seizures induced by acute lithium plus DOI but almost completely blocked seizures induced by acute lithium plus pilocarpine. This was surprising since seizures induced by acute lithium plus DOI were less severe than those after acute lithium plus pilocarpine, but myo-inositol was more effective in blocking the latter. Epi-inositol also blocked seizures under both conditions but it was less effective than myo-inositol after treatment with acute lithium plus pilocarpine. The latencies to seizures and/or severity of seizures were potentiated more by chronic than acute lithium pretreatment with both DOI and pilocarpine, but attenuation by myo-inositol was less with each agonist after chronic lithium compared with acute lithium treatment. Peripheral administration of a high dose of myo-inositol blocked seizures induced by acute lithium plus pilocarpine, but the inositol treatment itself was toxic and caused seizures prior to pilocarpine administration, so the mechanism of action cannot simply be attributed to increased brain inositol levels. These results demonstrate that lithium modulates the in vivo responses to DOI and pilocarpine, most probably through an effect on the phosphoinositide signal transduction system. They also show that centrally administered myo-inositol modifies responses to these agents, but the effectiveness of epi-inositol and other results leave unclear the mechanistic basis of its actions.

Amphetamines↗
PubMed2005

Recent advances in elucidating pain mechanisms.

PURPOSE OF REVIEW: The purpose of this review is to highlight the important recent advances in this fast developing field of pain mechanisms. It is now recognized that acute tissue and neural injuries can result in nociceptor sensitization (primary hyperalgesia) and spinal cord hyperexcitability or central sensitization that results in secondary hyperalgesia and allodynia. RECENT FINDINGS: New findings regarding peripheral and central sensitization are presented in this review. Newer ideas on pain modulation, pain states and pain syndromes, mechanisms of chronic pain, newer opioid and non opioid medications including newer N-methyl-D-asparate antagonists, cyclooxygenase-2 inhibitors and membrane stabilizing analgesics as well as pain control at the genetic level are discussed. SUMMARY: The research of the last decade has focused on the biochemical and structural plasticity of the nervous system following tissue and nerve injury. The mechanisms involved in the transition from acute to chronic pain are complex with the involvement of interacting receptor systems and intracellular ion flux, second messenger systems, new synaptic connections and apoptosis.

Journal Article↗
PubMed2005

Diversity of ovarian steroid signaling in the hypothalamus.

It is well known that many of the actions of gonadal steroids in hypothalamic neurons are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. Since the cloning of the intracellular steroid receptors/transcription factors, it has been assumed that most if not all of the actions of the gonadal steroids are mediated via these intracellular receptors. However, there now exist compelling evidence for membrane (G-protein-coupled) steroid receptors for estrogen and progesterone in hypothalamic and other brain neurons. But, it is not well understood how steroids signal via membrane receptors, and how these signals impact not only membrane excitability but also gene transcription in hypothalamic neurons. Indeed, it has been known for sometime that gonadal steroids can rapidly alter hypothalamic neuronal activity within seconds, indicating that some cellular effects can occur via membrane delimited events. In addition, gonadal steroids can affect second messenger systems, including calcium and various kinases to prompt and/or alter cell signaling. Therefore, this chapter will consider our current knowledge of rapid (i.e., seconds to minutes) membrane-initiated and intracellular signaling as well as classical nuclear receptor signaling by gonadal steroids in hypothalamic neurons, the nature of these receptors and how they contribute to homeostatic functions.

Animals↗
PubMed1998

Somatostatin as a neurotrophic factor. Which receptor/second messenger transduction system is involved?

A variety of studies support a trophic role for somatostatin in the developing nervous system, evidenced as stimulation of neurite outgrowth and axonal or neuronal migration in both in vivo and culture models. Cloning experiments have now demonstrated the existence of five subtypes of somatostatin receptor, differentially distributed in the nervous system, differentially linked to specific signal transduction systems and in certain cases differentially expressed during development. The combination of the differential and developmental regulation of expression of both the somatostatin peptides and their receptors thus provides great potential in terms of trophic effects. To substantiate trophic effects of somatostatin, data are presented from two different model systems, cultures of cerebellar granule cells as well as transgenic mice in which somatostatin is expressed under the control of the glial fibrillary acidic protein promoter. Finally, potential receptor subtypes and second messenger systems involved in these trophic effects are addressed.

Animals↗
PubMed1997

[Blood pressure-regulating factor vasopressin].

The DNA of AVP vasopressin (AVP) is composed of 3 exons (A, B, C) and 2 introns (I, II). Following transcription, translation, and processing AVP(MW 1081) is produced. AVP receptors (VR) are classified into V1aR, V1bR and V2R. V1aR is composed of 418 amino acids (AA) and its MW is 46745. V1aR is in the vascular smooth muscle (VSM) and activates the phosphatidylinositol system, leading to the contraction of VSM. V1bR is composed of 424 AA and its MW 47034. It's second messenger systems are obscure, but V1bR is responsible for ACTH release. V2R is composed of 371 AA and its MW 40285. V2R is in the kidney and enhances the production of cAMP, leading to renal water and urea reabsorption.

Adrenocorticotropic Hormone↗
PubMed1992

cAMP-mediated second messenger mechanisms are involved in spinule formation in teleost cone horizontal cells.

A number of light adaptive changes of teleost horizontal cells are mediated by dopamine D1 receptors coupled positively with the cAMP second messenger system. Spinules, finger-like extensions from horizontal cell dendrites directed towards the cone pedicle cytoplasm, are formed in response to a stimulation of D1 receptors. We studied the second messenger mechanism associated with this process using isolated dark-adapted cyprinid retinae. Increasing intracellular cAMP concentrations by adding a membrane permeable analogue, or by stimulating the adenylate cyclase and simultaneously blocking the degradation of cAMP, resulted in a significant increase of spinule numbers in spite of the absence of light. In contradistinction to using isolated retinae for pharmacological experiments, injection of drugs into the vitreous had inconsistent or negative results.

1-Methyl-3-isobutylxanthine↗
PubMed1994

[Platelet-activating factor-from molecular biology to clinic].

Platelet-activating factor (PAF) is not only a potent proinflammatory compound, but is also involved in cell proliferation and differentiation. cDNAs coding for PAF receptors were isolated in our laboratory from human, guinea-pig, rat, and mouse. They consist of 341-342 amino acids with 7 putative transmembrane domains, characteristic of a G-protein-coupled-receptor superfamily. The gene for the human PAF receptor is located on chromosome 1, and has three separate exons. By 5'-alternative splicing, two transcripts (leukocyte- and heart-type) were expressed under the direction of two distinct promoters. Signal transduction of the PAF receptor disclosed that it couples with many effector systems including phospholipase C activation, inhibition of adenylate cyclase, MAP kinase activation, and phospholipase A2 activation. The multiplicify of these second messenger systems allows PAF to have a variety of biological activities, even though it is a single molecule and has no receptor subtypes.

Amino Acid Sequence↗
PubMed1994

Pre- and postsynaptic changes mediated by two second messengers contribute to expression of Aplysia long-term heterosynaptic inhibition.

FMRFamide evokes long-term inhibition of the sensorimotor connection of Aplysia that includes structural alterations in the presynaptic sensory cell. FMRFamide also evokes a down-regulation of the adhesion molecule apCAM from the surface of the postsynaptic motor cell L7. We examined the second messenger pathways mediating the long-term actions of FMRFamide on both the pre- and postsynaptic cells and determined whether the activation of each pathway is required for the expression of long-term functional and structural plasticity. Inhibition of the lipoxygenase pathway of arachidonic acid metabolism, but not the cyclooxygenase pathway, blocks the long-term changes in the presynaptic sensory cell evoked by FMRFamide. The down-regulation of apCAM in L7 appears to be mediated by cAMP-dependent activation of protein kinase A. Blocking the cAMP-dependent changes also blocks FMRFamide-induced long-term functional and structural changes. These results suggest that the expression of long-term heterosynaptic inhibition in Aplysia may require concomitant presynaptic and postsynaptic changes, each transduced by specific second messenger systems.

Animals↗
PubMed2004

Regulation of intestinal secretion involved in the interaction between neurotransmitters and prostaglandin E2.

In this short review, it will be described that neurotransmitter-induced secretion in the intestine may be influenced by the tissue level of prostaglandin E2 (PGE2). In the normal condition, vasoactive intestinal polypeptide (VIP) and acetylcholine (ACh) are the predominant neurotransmitters of secretomotor neurones. VIP and ACh activate distinct second messenger systems in epithelial cells, i.e. adenosine 3', 5'-cyclic monophosphate (cAMP) and calcium ion (Ca2+), respectively. An increase in intracellular cAMP induces a small amount of chloride (Cl-) secretion in epithelial cells, while simultaneous increases in intracellular Ca2+ and cAMP greatly enhances the cAMP-induced Cl- secretion. When the concentration of prostaglandins reaches a high level in the intestinal tissue substance P, which is a neurotransmitter of sensory neurones, can also induce a massive Cl- secretion by cross-potentiation of cAMP and Ca2+ in epithelial cells. In conclusion, it is considered that the concentration of tissue PGE2 may indicate tissue alert level, and when this level elevates, PGE2 enhances ACh and SP-induced Cl- secretion, thus mediating massive fluid secretion for host defence.

Animals↗
PubMed1990

Involvement of the phosphoinositol (PI) system in the mechanism of hormonal imprinting.

Certain components of the phosphoinositol (PI) system are present in the unicellular Tetrahymena. Treatment of Tetrahymena with insulin did not alter the relative proportions of the examined six phospholipid components (PIP2, PIP, phosphatidylcholine, phosphatidylethanolamine, PI, PA), but the primary interaction (imprinting) with insulin accounted for an about 75% decrease in the PIP2-level and an about 20% increase in the phosphatidylethanolamine level. The experimental results strongly suggest that hormonal imprinting accounted for adjustment of the second messenger systems of Tetrahymena to an energy saving level.

Animals↗
PubMed1995

Effects of choline and ethanolamine on the synthesis and breakdown of the inositol phospholipid (PI) system in Tetrahymena.

Lower concentrations of choline chloride and ethanolamine (10(-3) M; 10(-5) M) increased phosphatidyl inositol (PI), phosphatidyl inositol monophosphate (PIP) and phosphatidyl inositol bisphosphate (PIP2) level of Tetrahymena, while higher concentrations (10(-2) M) decreased them. These two substances also influenced, however in a less obvious way, the transformation of inositol phospholipids. The experiments draw attention to the sensitivity of the precursors of the second messenger system at a phylogenetically low level.

Animals↗
PubMed1992

Taurine receptor: kinetic analysis and pharmacological studies.

A new procedure for the preparation of the taurine receptor from mammalian brain is described. The taurine receptor thus prepared shows a Kd of 92 nM, Bmax of 6.0 pmol/mg protein and Hill coefficient of 0.90 suggesting a single site model for the binding of 3H-taurine to the receptor. The binding of 3H-taurine to the receptor is highly specific and is not affected by agonists and antagonists of other receptors such as glutamate, quisqualic acid, kainate and NMDA for the glutamate receptor; glycine and strychnine for the glycine receptor; FNZP for the benzodiazepine receptor; picrotoxin and bicuculline for the GABAB receptor. However, analogues of taurine (e.g., homotaurine and hypotaurine) are potent inhibitors inhibiting more than 50% of 3H-taurine binding at 0.1 microM. Taurine receptor binding is not significantly affected by monovalent cations (e.g., Na+, K+, Li+ and NH4+) at 1 mM or divalent cations (e.g., Mg2+, Ca2+, Ba2+ and Mn2+) at 0.1 mM. However, the binding was completely abolished by Co2+, Zn2+ and Hg2+ at 0.1 mM, suggesting the presence of free sulfhydryl groups near or at the ligand binding site. Among the amino acids tested, cysteic acid was the most potent inhibitor, followed by beta-alanine, valine, tyrosine and cysteine inhibiting 3H-taurine to an extent of 84, 66, 63, 62, and 58% of 1 mM, respectively. Nucleotides and second messengers (e.g., ATP, ADP, cAMP, GTP, cGMP and diacyl glycerol) do not inhibit 3H-taurine binding significantly at 0.1 mM. From above studies, it seems that the taurine receptor is not up- or down-regulated by ions or second messengers at the taurine binding site. Whether the taurine receptor is coupled to a G-protein mediated second messenger system is currently under investigation.

Amino Acids↗
PubMed1995

Cloning and functional expression of a cDNA encoding a human type 2 neuropeptide Y receptor.

Neuropeptide Y (NPY) is a 36-amino acid polypeptide that is widely distributed in the central nervous system and periphery. Pharmacological studies have suggested that there are at least three receptor subtypes, Y1, Y2, and Y3. Cloning of the Y1 subtype has been reported previously. Here we report the isolation by expression cloning of a cDNA encoding a human NPY receptor displaying a pharmacology typical of a Y2 receptor. COS-7 cells transfected with the cDNA express high affinity binding sites for NPY, peptide YY, and NPY13-36, whereas [Leu31,Pro34]NPY binds with lower affinity. The receptor is 381 amino acids in length and has seven putative transmembrane regions typical of G-protein-coupled receptors. Comparison of the amino acid sequence of this Y2 receptor to that of the human Y1 receptor indicates that the two receptors are 31% identical at the amino acid level. Northern blot analyses reveal a single 4-kilobase mRNA species and indicate that the messenger RNA is present in many areas of the central nervous system. NPY induced calcium mobilization and inhibited forskolin-stimulated cAMP accumulation in Chinese hamster ovary cells that stably express the Y2 receptor cDNA, indicating that the recombinant Y2 receptor is functionally coupled to second messenger systems.

Amino Acid Sequence↗
PubMed1997

O2 availability modulates transmembrane Ca2+ flux via second-messenger pathways in anoxia-tolerant hepatocytes.

Transmembrane Ca(2+)-flux was studied from single isolated turtle hepatocytes by using a noninvasive Ca(2+)-selective self-referencing microelectrode. Cells in Ca(2+)-reduced culture medium demonstrated a vanadate- and lanthanum-inhibitable Ca(2+)-efflux of 4 x 10(-17) mol Ca2+. microns-2. s-1 continuously over 170 h. This flux diminished with 50 nM phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator, and was reinstated on PKC deactivation with sphingosine. Progressive hypoxia resulted in a reversible suppression of Ca2+ efflux to 90% of normoxic controls with an apparent Michaelis constant for oxygen of 145 microM. PKC activation was critical in this suppression, as anaerobic administration of sphingosine caused a Ca2+ influx and cell rupture. Hypoxia was also associated with an altered pattern of adenosine-mediated control over Ca2+ efflux. Adenosine (100 microM) elevated Ca2+ efflux twofold in normoxia, but neither adenosine nor the A1-purinoreceptor antagonist 8-phenyltheophylline altered the observed anaerobic suppression. Aerobic administration of 2-10 mM KCN failed to reproduce the anaerobic suppression; however, in conjunction with 10 mM iodoacetate, complete metabolic blockade caused a Ca2+ influx and cell rupture. These observations suggest modulatory control by oxygen over transmembrane Ca2+ efflux involving second-messenger systems in the hypoxic transition.

Animals↗
PubMed1990

In vitro modulation of porcine Leydig cell steroidogenesis by phorbol-12-myristate-13-acetate and 1,2-dioctanoylglycerol.

Serum-free primary cultures of neonatal (1-day-old) porcine Leydig cells were used to study the effects of phorbol-12-myristate-13-acetate and 1,2-dioctanoylglycerol on testosterone and pregnenolone production. Phorbol-12-myristate-13-acetate alone from 0.001-10 mumol/l stimulated testosterone and pregnenolone production, whereas 1,2-dioctanoylglycerol alone had no effect on steroid production, relative to control. Phorbol-12-myristate-13-acetate and 1,2-dioctanoylglycerol each inhibited pLH-stimulated testosterone and pregnenolone production. To further clarify the influence of these protein kinase C activators on steroidogenesis, cultured Leydig cells were treated with either phorbol-12-myristate-13-acetate or 1,2-dioctanoylglycerol plus forskolin (an adenylate cyclase activator). Both phorbol-12-myristate-13-acetate and 1,2-dioctanoylglycerol inhibited forskolin-stimulated testosterone production. Phorbol-12-myristate-13-acetate had no effect on forskolin-stimulated pregnenolone production and only the highest concentration of 1,2-dioctanoylglycerol (100 mumol/l) inhibited forskolin-stimulated production of pregnenolone. These data demonstrate that porcine Leydig cell steroidogenesis can be modulated by interactions of the protein kinase C and protein kinase A second messenger systems.

Animals↗