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PubMedDate not supplied

Vasoactive intestinal polypeptide modulates GABAA receptor function through activation of cyclic AMP.

Vasoactive intestinal polypeptide (VIP) has been shown to potentiate current responses elicited by activation of the GABAA receptor (IGABA) in freshly dissociated ganglion cells of the rat retina. Here we tested the hypothesis that this heteroreceptor cross talk is mediated by an intracellular cascade of events that includes the sequential activation of a stimulatory guanine nucleotide binding (Gs) protein and adenylate cyclase, the subsequent increase in levels of cyclic AMP and, finally, the action of the cyclic AMP-dependent protein kinase (PKA). Intracellular dialysis of freshly dissociated ganglion cells with GTP gamma s irreversibly potentiated IGABA, while GDP beta s either decreased or had no effect on IGABA. Additionally, GDP beta s blocked the potentiation of IGABA by VIP. Cholera toxin rendered VIP ineffective in potentiating IGABA, while pertussis toxin had no effect on the VIP-induced potentiation of IGABA. Extracellular application of either forskolin or 8-bromo-cyclic AMP potentiated IGABA, as did the introduction of cyclic AMP directly into the intracellular compartment through the recording pipet. Intracellular application of cyclic AMP-dependent protein kinase (PKA) potentiated IGABA, while a PKA inhibitor blocked the potentiating effect of VIP. These results lead us to conclude that activation of a cyclic AMP-dependent second-messenger system mediates the modulation of GABAA receptor function by VIP in retinal ganglion cells.

Animals↗
PubMed1993

Guanylate cyclase activity in male pattern baldness. Stimulating effect of 3-beta-androstanediol.

Guanylate cyclase (GC) activity was measured in the cytosolic fraction of sebaceous gland-enriched skin samples obtained from alopecic and non-alopecic areas of subjects affected by male pattern baldness. GC activity was significantly higher in alopecic scalp (7.13 +/- 2.7 pmol/min/mg prot; n = 22) than in non-alopecic samples (3.91 +/- 0.48 pmol/min/mg prot; n = 8). 3-beta-androstanediol was able to increase GC activity up to 15% when added to the incubation medium (1 x 10(-5) M). The regional differences observed should be due to the larger size of the sebaceous glands in alopecic areas. The higher production of dihydrotestosterone and 3-beta-androstanediol in alopecic areas may also contribute to determine the level of GC in scalp skin. The role of second messenger systems in sebaceous glands to understand certain aspects of the action mechanism of androgens is discussed.

Alopecia↗
PubMed1989

Modulation of second messenger function in rat brain by in vivo alteration of receptor sensitivity: relevance to the mechanism of action of electroconvulsive therapy and antidepressants.

1. The second messengers cyclic AMP and inositol triphosphate are the intracellular mediators for a number of neurotransmitters for which receptors exist on brain neurons. 2. Up- or down-regulation of these receptors in general produce corresponding changes in the associated second messenger systems. 3. Chronic administration of antidepressants including electroconvulsive shock to rats produces a number of changes in cerebral receptors, notably down-regulation of beta-adrenergic and serotonin 5-HT2 receptors and up-regulation of alpha-1 adrenergic receptors. 4. The changes in receptor number induced by such antidepressant treatments are in general accompanied by corresponding changes in the associated second messenger reactions. 5. Antidepressant administration has also been shown to induce increased post-receptor mediated adenylate cyclase activity in cortical membranes, and similar effects have also been reported in striatum after chronic administration of neuroleptics. The relevance of these effects to the mechanism of action of the drugs is discussed.

Animals↗
PubMed1993

cAMP-dependent and tissue-specific expression of genes encoding steroidogenic enzymes in bovine luteal and granulosa cells in primary culture.

Steroidogenic enzymes are differentially expressed throughout the ovarian cycle. The complex pattern of cell-specific up- and down-regulation accounts, at least in part, for the cyclic production of estrogens, androgens and progesterone. The gonadotropins follicle-stimulating hormone and luteinizing hormone are the main regulators of ovarian steroid hormone production and act primarily via the cAMP second-messenger system. Previous studies have identified cAMP-responsive sequences (CRS) in a number of genes encoding steroidogenic enzymes. In the present study we attempted to compare the cAMP responsiveness of some of these sequences with each other and with the classical cAMP-response element (CRE), as identified in the somatostatin gene. In addition, we were interested to determine whether or not the information for tissue-specific expression is contained by these sequences. Using transient transfection of reporter gene constructs, comprising the CRS of bCYP11A, bCYP17, hCYP21B and bovine adrenodoxin, we investigated cAMP-dependent and tissue-specific expression in primary cultures of bovine luteal and granulosa cells. Treatment of transfected luteal cells with forskolin markedly increased the expression of all but the CYP17-specific reporter gene constructs. A similar pattern of forskolin responsiveness was observed when these reporter gene constructs were transfected in bovine granulosa cells in primary culture. Furthermore, when a reporter gene construct containing the classical CRE genomic was transfected in bovine luteal cells, its expression was also highly stimulated upon treatment with forskolin. Thus, the classical cAMP/CRE system appears to be functional in these cells. Northern blot analysis of primary cultures of bovine luteal and granulosa cells revealed that bCYP17 and bCYP21B are not expressed in control and forskolin-treated cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenodoxin↗
PubMed2006

Binding sites of crustacean hyperglycemic hormone and its second messengers on gills and hindgut of the green shore crab, Carcinus maenas: a possible osmoregulatory role.

To determine the possible involvement of crustacean hyperglycemic hormone (CHH) in osmoregulation in crustaceans, ligand binding and second messenger assays were performed on gills and hindgut preparations of the green shore crab Carcinus maenas, whilst midgut gland, previously known as one of the target tissues of CHH served as a control tissue. Classical receptor binding analyses using [(125)I]CHH by saturation and displacement experiments from membrane preparations from gills, hindgut, and midgut glands demonstrated that CHH binding characteristics involved one site, highly specific, saturable, and displaceable kinetics: (gills: K(D) 5.87 +/- 2.05 x 10(-10) and B(MAX) 6.50 +/- 1.15 x 10(-10), hindgut: K(D) 3.54 +/- 1.49 x 10(-10) and B(MAX) 2.31 +/- 0.44 x 10(-10), and midgut gland: K(D) 7.28 +/- 0.9 x 10(-10) and B(MAX) 3.28 +/- 0.25 x 10(-10)) all expressed as M/mg protein. No differences, in terms of displacement were observed between the two CHH isoforms (N-terminally blocked pGlu and unblocked Gln) variants. CHH binding sites appeared to be coupled to a second messenger system involving cGMP in all the tissues examined. Exposure of crabs to dilute seawater increased levels of cGMP, glucose in gills and circulating CHH levels. Other crustacean neuropeptides including crustacean cardioactive peptide, molt inhibiting hormone, L-enkephalin, FMRF-amide, proctolin, and crustacean hyperglycemic hormone precursor-related peptide were tested with regard to possible osmoregulatory roles with reference to changes in second messenger (cAMP and cGMP) concentrations in gill, hindgut, and midgut tissues in vitro, following application at 2 x 10(-8) M but all were found to be inactive. Thus, it seems likely that CHH is a pertinent neurohormone involved in osmoregulation, thus expanding its many functions as a pleiotropic hormone in crustaceans.

Animals↗
PubMed2001

Malignant hyperthermia.

Malignant hyperthermia is an autosomal-dominant inherited disorder of the skeletal muscle cell characterized by a hypermetabolic response to all commonly used inhalational anaesthetics and depolarizing muscle relaxants. The clinical syndrome includes muscle rigidity, hypercapnia, tachycardia and myoglobinuria as result of increased carbon dioxide production, oxygen consumption and muscle membrane breakdown. In human beings and animals susceptible to malignant hyperthermia, it is generally accepted that an increase in the level of myoplasmic free calcium is the cause of the syndrome. Various hypotheses have been proposed to account for the increase of intracellular calcium levels, e.g. a defect in the calcium release channel of the sarcoplasmic reticulum (ryanodine receptor), an abnormality of the excitation-contraction coupling mechanisms, or alterations in second messenger systems of skeletal muscles. This review gives an overview of the main features of this disease and recent advances in research including pathophysiology, treatment, diagnosis and genetics as well as association with other disorders.

Anesthesia↗
PubMed1998

Interaction of reactive oxygen species with ion transport mechanisms.

The use of electrophysiological and molecular biology techniques has shed light on reactive oxygen species (ROS)-induced impairment of surface and internal membranes that control cellular signaling. These deleterious effects of ROS are due to their interaction with various ion transport proteins underlying the transmembrane signal transduction, namely, 1) ion channels, such as Ca2+ channels (including voltage-sensitive L-type Ca2+ currents, dihydropyridine receptor voltage sensors, ryanodine receptor Ca2+-release channels, and D-myo-inositol 1,4,5-trisphosphate receptor Ca2+-release channels), K+ channels (such as Ca2+-activated K+ channels, inward and outward K+ currents, and ATP-sensitive K+ channels), Na+ channels, and Cl- channels; 2) ion pumps, such as sarcoplasmic reticulum and sarcolemmal Ca2+ pumps, Na+-K+-ATPase (Na+ pump), and H+-ATPase (H+ pump); 3) ion exchangers such as the Na+/Ca2+ exchanger and Na+/H+ exchanger; and 4) ion cotransporters such as K+-Cl-, Na+-K+-Cl-, and Pi-Na+ cotransporters. The mechanism of ROS-induced modifications in ion transport pathways involves 1) oxidation of sulfhydryl groups located on the ion transport proteins, 2) peroxidation of membrane phospholipids, and 3) inhibition of membrane-bound regulatory enzymes and modification of the oxidative phosphorylation and ATP levels. Alterations in the ion transport mechanisms lead to changes in a second messenger system, primarily Ca2+ homeostasis, which further augment the abnormal electrical activity and distortion of signal transduction, causing cell dysfunction, which underlies pathological conditions.

Animals↗
PubMed1989

Receptor-operated calcium-permeable channels in vascular smooth muscle.

The extracellular Ca2+ dependence of agonist stimulation of vascular smooth muscle (VSM) has been investigated in rat cultured aortic smooth muscle cells (SMCs) and isolated mesenteric resistance vessels (MRVs). Agonists such as [Arg8]vasopressin (AVP), angiotensin II (Ang II), and adenosine-5'-triphosphate (ATP) stimulated 45Ca2+ entry into the SMCs that was (a) independent of the extent to which the membranes were polarized, and (b) was not inhibited by organic Ca2+ channel antagonists. Measuring the intracellular Ca2+ concentration [( Ca2+]i) after stimulation with agonists revealed a rapid increase of [Ca2+]i, which was followed by a sustained rise that was insensitive to Ca2+ antagonists. In Ca2+-free medium, only the initial peak of [Ca2+]i was still observed, but the sustained response to the agonists disappeared completely. This observation indicates that the sustained elevation seen in Ca2+-containing medium was the consequence of agonist-induced Ca2+ entry. In MRVs, a corresponding Ca2+-antagonist-insensitive, agonist (norepinephrine and AVP)-induced tonic tension was also identified. Moreover, agonists were able to induce sustained tension in the MRVs regardless of whether the membrane was normally polarized or was previously depolarized (80 mM K+) upon their administration. The agonist-stimulated 45Ca2+ entry in the SMCs could be blocked by the multivalent cations La3+, Cd2+, Mn2+, Co2+, Ni2+, and Mg2+ (in this order of potency). Depolarization-induced 45Ca2+ influx was inhibited by these cations in the same order of potency, but was significantly more sensitive to Cd2+ and significantly less sensitive to La3+ than that stimulated by agonists. Treatment with 2-nitro-4-carboxyphenyl-N,N-diphenyl-carbamate (NCDC, a proposed inhibitor of phospholipase C) reduced both the agonist-induced 45Ca2+ influx and the sustained elevation of [Ca2+]i in the SMCs. NCDC also abolished both contraction and depolarization induced by agonists in the MRVs. The kinase C stimulator phorbol-12-myristate-13-acetate (PMA) inhibited the agonist-induced 45Ca2+ influx and sustained increase in [Ca2+]i in the SMCs, whereas the kinase C inhibitor staurosporine had no effect. In the MRVs, in contrast, PMA had no influence on agonist-induced contractions. Staurosporine (1 microM), however, completely prevented these contractions, as did NCDC, but, unlike NCDC, it did so without affecting the agonist-induced depolarization. These data support an important role of receptor-operated Ca2+-permeable channels in VSM activation by agonists and suggest that these channels may be controlled by intracellular enzymic pathways and second messenger systems.

Animals↗
PubMed1990

Induction of differentiation of rat retinal, germinal, neuroepithelial cells by dbcAMP.

Little is known about the factors that regulate the production of neurons during the development of the vertebrate central nervous system (CNS); however, evidence from several neuronal cell lines suggests that an increase in intracellular cAMP might trigger the process of differentiation. To determine if a similar process is involved in differentiation during normal CNS neurogenesis, we raised the intracellular level of cAMP in primary cultures of mitotically active, germinal neuroepithelial cells from fetal and postnatal rat retina. This treatment induced differentiation of the CNS precursors, causing the cells to cease DNA synthesis and increase their expression of proteins normally found in differentiated retinal cells. These results indicate that germinal neuroepithelial cell differentiation can be controlled through the cAMP second messenger system, and that the regulation of this system may in part determine the numbers and ratios of the various classes of neurons during the normal development of the CNS.

Animals↗
PubMed1993

Thapsigargin blocks the mobilisation of intracellular calcium caused by activation of human NK1 (long) receptors expressed in Chinese hamster ovary cells.

Neurokinin receptors can couple to several second messenger systems including phospholipase C and intracellular calcium mobilisation. Using FURA-2 microspectrofluorimetry, this study examines the mobilisation of calcium in CHO cells which had been stably transfected with the long isoform of the human NK1 receptor. Substance P caused a concentration-dependent rise in inositol phosphate production which was correlated with a reversible increase in intracellular calcium levels. The mobilisation of calcium was reduced by the removal of extracellular calcium from the bathing solution, and almost totally abolished by depletion of intracellular calcium pools with 1 microM thapsigargin. These data suggest that the transduction mechanism associated with NK1 (long) receptor activation can utilise both intracellular and extracellular calcium pools in this expression system.

Animals↗
PubMed1998

Fibroblast growth factor receptor signaling in Xenopus retinal axon extension.

Fibroblast growth factor receptors (FGFRs) and N-cadherin both regulate axon extension in developing Xenopus retinal ganglion cells (RGCs). Cultured cerebellar neurons have been shown to require FGFR activity for N-cadherin-stimulated neurite outgrowth, raising the possibility that N-cadherin is a FGFR ligand. To investigate this possibility in the developing visual system, retinal neurons were transfected with a dominant-negative FGFR (XFD) and plated on purified N-cadherin substrates. XFD-expressing neurons extended markedly shorter processes than control GFP-expressing neurons, implicating a role for FGFRs in N-cadherin-stimulated neurite outgrowth. To examine whether N-cadherin and FGFRs share the same pathway or use distinct second messenger pathways, specific inhibitors of implicated signaling molecules were added to neurons stimulated by N-cadherin, basic fibroblast growth factor (bFGF), or brain-derived nerve factor (BDNF) (which stimulates RGC outgrowth by a FGFR-independent mechanism). Diacylglycerol (DAG) lipase and Ca2+/calmodulin kinase II inhibitors both significantly reduced outgrowth stimulated by N-cadherin or bFGF but not by BDNF. Furthermore, we show that inhibiting DAG lipase activity in RGC axons extending in vivo toward the optic tectum reversibly slows axon extension without collapsing their growth cones. Thus, a common second-messenger signaling pathway mediating both N-cadherin- and bFGF-stimulated neurite extension is consistent with a model in which N-cadherin directly modulates the FGFR or a model whereby both FGFR and N-cadherin regulate the same second-messenger system.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Epidermal growth factor antagonizes vasopressin in vivo and in vitro.

Since EGF causes diuresis through a renal action and may antagonize the hydroosmotic effect of AVP in vitro we investigated the antagonistic action of EGF with AVP in vivo and the mechanism of the antagonism in vitro. Conscious ewes received i.m. injections of a selective AVP V2-receptor agonist (1-desamino, D-Arg8 vasopressin acetate, DDAVP) every 12 hours for days 5 to 16. All ewes received an i.v. isotonic saline infusion (100 ml/day) for days 1 to 8 and days 13 to 16, and i.v. EGF in 100 ml saline/day at doses of 0 (N = 8) or 10 (N = 8) micrograms/hr for days 9 to 12. DDAVP reduced both urine volume and water intake, and increased urine osmolality. In contrast, simultaneous infusion of EGF reversed the DDAVP-induced responses, resulting in a transient negative fluid balance, kaliuresis and a transient natriuresis (all P < 0.05). When EGF treatment ceased, the effects of DDAVP treatment alone gradually became apparent. From the in vitro studies, the AVP-related peptides displaced specific AVP V1- and V2-receptor antagonist radioligands from rat renal inner medullary membranes, whereas EGF had no effect. However, EGF antagonized AVP V2-stimulated cAMP production in a dose-dependent way (IC50 = 2 x 10(-7) M). Therefore, the diuretic effect of EGF is not via direct antagonism of the antidiuretic AVP V2-receptor but seems mediated by inhibition of the antidiuretic AVP V2-receptor second messenger system.

Animals↗
PubMedDate not supplied

Excitatory amino acids modulate phosphoinositide signal transduction in human epileptic neocortex.

Stimulation of phosphoinositide (PI) hydrolysis by norepinephrine (NE), carbachol (Carb), and excitatory amino acids (EAAs) was measured in slices prepared from neocortex excised during epilepsy surgery. NE and Carb markedly enhanced PI turnover (EC50: NE, 12 microM; Carb, 661 microM) as reflected by [3H]inositol monophosphate (IP1) accumulation in tissue slices prelabeled with [3H]myoinositol. These effects were dose-dependent, saturable, and five to six times higher than basal IP1 accumulation. A weaker stimulation (twofold) was observed with quisqualate (QUIS; EC50, 1.1 microM) and glutamate (GLU; EC50, greater than 1 mM), while minimal or no stimulation was seen with kainate (KA) and N-methyl-D-aspartate (NMDA). Agonist-stimulated PI turnover was significantly reduced in samples from actively spiking epileptic neocortex versus nonspiking areas as defined by electrocorticography (NE, -23%, p less than 0.05; Carb, -44%, p less than 0.01). Preincubation of slices with various EEAs inhibited Carb-induced IP1 formation. The maximal extent of inhibition (1 mM) was both amino acid-dependent (IC50: NMDA, 5 microM; KA, 3.3 microM; QUIS, 47 microM; GLU, greater than 1 mM). These data suggest that epileptic activity modulates PI metabolism and alters receptor-effector coupling. As important mediators of epileptogenesis, EAAs may interfere++ with the efficiency of this second messenger system.

Carbachol↗
PubMed1990

Suppression by glutamate of cGMP-activated conductance in retinal bipolar cells.

Depolarizing bipolar cells (DBCs) of the retina are the only neurons in the vertebrate central nervous system known to be hyperpolarized by the neurotransmitter glutamate. Both glutamate and its analogue L-2-amino-4-phosphonobutyrate (APB) hyperpolarize DBCs by decreasing membrane conductance. Furthermore, glutamate responses in DBCs slowly decrease during whole-cell recording, suggesting that the response involves a second messenger system. Here we report that intracellular cyclic GMP or GTP activates a membrane conductance that is suppressed by APB, resulting in an enhanced APB response. In the presence of GTP-gamma-S, APB causes an irreversible suppression of the conductance. Inhibitors of G-protein activation or phosphodiesterase activity decrease the APB response. Thus, the DBC glutamate receptor seems to close ion channels by increasing the rate of cGMP hydrolysis by a G protein-mediated process that is strikingly similar to light transduction in photoreceptors.

1-Methyl-3-isobutylxanthine↗
PubMed1992

The cellular toxicity of aluminium.

Aluminium is a serious environmental toxicant and is inimical to biota. Omnipresent, it is linked with a number of disorders in man including Alzheimer's disease, Parkinson's dementia and osteomalacia. Evidence supporting aluminium as an aetiological agent in such disorders is not conclusive and suffers principally from a lack of consensus with respect to aluminium's toxic mode of action. Obligatory to the elucidation of toxic mechanisms is an understanding of the biological availability of aluminium. This describes the fate of and response to aluminium in any biological system and is thus an important influence of the toxicity of aluminium. A general theme in much aluminium toxicity is an accelerated cell death. Herein mechanisms are described to account for cell death from both acute and chronic aluminium challenges. Aluminium associations with both extracellular surfaces and intracellular ligands are implicated. The cellular response to aluminium is found to be biphasic having both stimulatory and inhibitory components. In either case the disruption of second messenger systems is observed and GTPase cycles are potential target sites. Specific ligands for aluminium at these sites are unknown though are likely to be proteins upon which oxygen-based functional groups are orientated to give exceptionally strong binding with the free aluminium ion.

Aluminum↗
PubMed1997

Parathyroid hormone stimulates calcium influx and the cAMP messenger system in rat enterocytes.

Direct effects of parathyroid hormone (PTH) on calcium uptake by isolated rat duodenal cell preparations enriched in enterocytes were investigated. PTH significantly stimulated enterocyte 45Ca2+ influx in a time-dependent (1-10 min) manner and at all doses tested (2 x 10(-13) to 10(-7) M). The Ca2+ channel antagonists verapamil (10 microM) and nitrendipine (1 microM) completely blocked the stimulation of Ca2+ influx by the hormone (10(-8) M). PTH markedly increased cAMP levels in rat duodenal cells (88, 167, and 67%, after 1, 2, and 3 min, respectively). In agreement with these observations, forskolin (adenylate cyclase activator), dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP), and Sp-cAMPS (cAMP analogs) mimicked, whereas Rp-cAMPS (cAMP antagonist) suppressed PTH and DBcAMP activation of enterocyte calcium uptake. Furthermore, the effects of DBcAMP were abolished by nitrendipine. These results show direct rapid effects of PTH on duodenal cells' Ca2+ influx, which involve the activation of a dihydropyridine-sensitive Ca2+ influx pathway and the cAMP second messenger system.

Adenylyl Cyclases↗
PubMed1992

Glutathione: new candidate neuropeptide in the central nervous system.

The physiological significance of glutathione in the mammalian central nervous system is still uncertain, although some evidence indicates that it may be an important regulatory peptide. In the present study, the distribution and characteristics of glutathione binding sites in the brain have been studied. Biotinyl-glutathione was synthesized as a probe to detect glutathione binding sites in the CNS. Specific glutathione binding sites in the brain were largely localized to the white matter, suggesting the presence of glutathione receptors on neuroglial cells. The colloidal gold technique and immunofluorescence double staining allowed the visualization of the receptor at the cellular level and thus demonstrated that there are glutathione receptors on cultured astrocytes. Glutathione applied to cultured astrocytes elicited increased levels of intracellular inositol-1,4,5-trisphosphate, suggesting that glutathione receptors were coupled to phospholipase C. The localization of glutathione receptors on astrocytes and the activation of a second messenger system by glutathione suggest that glutathione may be a neuropeptide in the central nervous system.

Animals↗
PubMed1989

Mechanism of interleukin-2 signaling: mediation of different outcomes by a single receptor and transduction pathway.

The T cell lymphokine, interleukin-2 (IL-2), plays a pivotal role in an immune response by stimulating antigen-activated B lymphocytes to progress through the cell cycle and to differentiate into antibody-secreting cells. An IL-2 inducible B lymphoma line, in which the growth and differentiation responses are uncoupled, provides a model system for dissecting the signaling mechanisms operating in each response. This system was used to show that both signals are initiated by IL-2 binding to a single, unifunctional receptor complex. Moreover, both signals are transduced by a pathway that does not involve any known second messenger system and that can be blocked by a second T cell lymphokine, interleukin 4. These findings suggest that the pleiotrophic effects of IL-2 are determined by different translations of the signal in the nucleus.

Animals↗