Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the receptor mechanisms by which vasoactive intestinal polypeptide (VIP) and related peptides exert their effects on tyrosine hydroxylase (TH) gene expression. VIP, secretin, and peptide histidine isoleucine (PHI) each produced increases in TH gene expression, as measured by increases in TH mRNA levels and TH activity. The concentrations at which the effects of these peptides were maximal differed for TH activity and TH mRNA. Moreover, maximal increases in TH activity were 130-140% of control, whereas maximal increases in TH mRNA were 250% of control. The concentration dependence of the increases in TH mRNA in response to the three peptides was analyzed by fitting the data to nonlinear regression models that assume either one or two components to the response. The data for secretin fit best to a model that assumes a single component to the increase in TH mRNA levels. The data derived for PHI and VIP fit best to models that assumed two components to the TH mRNA response. These data suggested that there may be more than one receptor or signal transduction mechanism involved in the response to the various peptides. We examined whether the peptides exerted their effects through common or multiple second messenger systems. The ability of maximally active concentrations of these peptides to stimulate increases in TH mRNA was not additive, indicating that the peptides work through a common receptor or signal transduction pathway. Each peptide stimulated increases in protein kinase A (PKA) activity. Secretin and VIP were ineffective in increasing TH mRNA levels in a PKA-deficient mutant PC12 cell line (A126-1B2). Moreover, the adenylate cyclase antagonist 2',5'-dideoxyadenosine prevented the increase in TH mRNA produced by each peptide. Thus, each peptide requires an intact cyclic AMP second messenger pathway to produce changes in TH gene expression, suggesting that the complex pattern of response to VIP and PHI revealed by concentration-response analysis was due to the actions of these peptides at multiple receptors. To evaluate this possibility, we examined the effect of several peptide receptor antagonists on the increase in TH gene expression elicited by VIP, PHI, and secretin. The secretin antagonist secretin (5-27) (20 microM) had no significant effect on VIP or PHI stimulation of TH gene expression, but reduced the effect of secretin. The VIP antagonist VIP (10-28) (20 microM) reduced the effect of VIP on increasing TH mRNA, but had no significant effect on the response of TH mRNA to secretin or PHI.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Vasoactive intestinal polypeptide-related peptides modulate tyrosine hydroxylase gene expression in PC12 cells through multiple adenylate cyclase-coupled receptors. 809 40

bFGF is a neurotrophic protein expressed in various regions of the adult peripheral and central nervous system. The present study was undertaken to examine the role of bFGF in multihormonal, catecholaminergic and enkephalinergic cells of the adrenal medulla (AM). Western blot analysis revealed the presence of at least three bFGF isoforms (18, 22/23, and 24 kDa) in cultured bovine AM cells. Incubation of AM cells with the exogenous 18 kDa bFGF produced time-dependent increases in tyrosine hydroxylase (TH) and proenkephalin (PEK) mRNA, with maximal changes occurring at 12 h (TH) or 24 h (PEK) of bFGF exposure. Effects of bFGF on TH and PEK mRNA were non-additive with increases induced by exposure of AM cells to nicotine, the depolarizing agent veratridine, or the adenylate cyclase activator forskolin. These data indicate that bFGF effects may occur through intracellular pathways accessed during transsynaptic induction of TH and PEK genes. The increases in PEK mRNA induced by nicotine or bFGF were inhibited by the calcium antagonist TMB-8. TMB-8 also inhibited bFGF-induced increases in TH mRNA as well. However, treatment with TMB-8 increased basal levels of TH mRNA. The addition of bFGF increased endogenous levels of c-fos mRNA, c-Fos and c-Fos-related proteins, suggesting that bFGF may activate TH and PEK gene expression through a calcium-AP1 transcriptional regulatory pathway. Immunohistochemical analysis revealed the presence of bFGF-immunoreactivity (bFGF-IR) in the cytoplasm and in the nucleus of AM cells. Incubation of cells with exogenous bFGF produced time-dependent increases of nuclear bFGF-IR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Basic fibroblast growth factor (bFGF) regulates tyrosine hydroxylase and proenkephalin mRNA levels in adrenal chromaffin cells. 810 Jan 72

We previously reported that a factor(s) from rat choriocarcinoma (Rcho-1) cells suppresses circulating PRL levels and increases tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons in vivo. The purposes of this study were to determine whether this factor(s) increases tyrosine hydroxylase activity in fetal hypothalamic cells in vitro and to evaluate its chemical nature. The Rcho-1 cells are of placental origin and have the capacity to differentiate into giant cells and produce members of the placental PRL family. MMQ cells, a pituitary cell line that secretes PRL, and HRP-1, a placental cell line that does not produce any known members of the PRL family, were used as control cells. Tyrosine hydroxylase activity was assessed by incubation of hypothalamic cells for 1 h with 100 microM brocresine, an inhibitor of aromatic L-amino acid decarboxylase. Tyrosine hydroxylase activity was increased in a density-dependent manner when Rcho-1, but not HRP-1 or MMQ, cells were cocultured with hypothalamic cells for 24 h. Control and Rcho-1-stimulated tyrosine hydroxylase activities were markedly reduced with 1 mM alpha-methyl-p-tyrosine, a specific inhibitor of tyrosine hydroxylase. Tyrosine hydroxylase activity was not altered when hypothalamic cells were incubated for 24 h with rat PRL or recombinant rat placental lactogen-I, whereas a 24-h stimulation with 100,000 Rcho-1 cells and a 1-h stimulation with 5 mM (Bu)2cAMP increased tyrosine hydroxylase activity 3.7- and 3-fold, respectively. The magnitudes of the increase in tyrosine hydroxylase activity were similar when hypothalamic cells were cocultured with Rcho-1 cells for 1 and 24 h. Acetic acid extracts of Rcho-1, but not HRP-1 or MMQ, cells increased tyrosine hydroxylase activity within 1 h in a concentration-dependent manner. The 3-fold increase in tyrosine hydroxylase activity observed with 500,000 Rcho-1 cell equivalents was markedly reduced with 1 mM alpha-methyl-p-tyrosine. The mol wt range of the tyrosine hydroxylase-activating factor(s) (THAF) was estimated using ultrafiltration membranes. The majority of activity was found in the eluate from a 1,000 mol wt cut-off membrane. THAF activity in Rcho-1 cell extracts was decreased by preincubation with pronase, a nonspecific proteolytic enzyme, suggesting that the factor(s) is a peptide. THAF was resistant to inactivation by trypsin or chymotrypsin pretreatment. However, both enzymes destroyed the ability of pituitary adenylate cyclase-activating peptide, either alone or with Rcho-1 cell extracts, to increase tyrosine hydroxylase activity. Oxidation of Rcho-1 cell extracts with performic acid abolished THAF activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A factor(s) from a trophoblast cell line increases tyrosine hydroxylase activity in fetal hypothalamic cell cultures. 810 May 18

Signal-transduction pathways mediate a wide range of short-term changes in the physiology of neuronal systems from invertebrates to mammals. However, examples of long-term changes in neuronal physiology mediated by these pathways have been limited to invertebrate systems. In this report, long-term changes in the physiology of mammalian neurons were studied by using genetic intervention to cause a long-lasting activation of the cAMP pathway. The catalytic domain of yeast adenylate cyclase (cyr), encoding a constitutive enzyme activity, was expressed in neuronal cells infected with a defective herpes simplex virus vector (pHSVcyr). In PC-12 cells infected with pHSVcyr, increases were seen in cAMP levels, protein kinase A activity, protein phosphorylation, phosphorylation of the tyrosine hydroxylase protein kinase A site (Ser40), and catecholamine release. Infection of sympathetic neurons with pHSVcyr increased cAMP levels, protein phosphorylation, and catecholamine release. Yeast adenylate cyclase immunoreactivity and elevated cAMP levels were localized to the cell bodies of sympathetic neurons. The increase in neurotransmitter release was both Ca(2+)- and activity-dependent and persisted for at least 1 week after infection of the sympathetic neurons, suggesting that sustained physiological activation of the cAMP pathway may mediate long-term changes in the neuronal physiology of mammalian systems.
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PMID:Long-term increases in neurotransmitter release from neuronal cells expressing a constitutively active adenylate cyclase from a herpes simplex virus type 1 vector. 810 99

Expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine (CA) synthesis, was studied in quail neural crest (NC) cultures to investigate the role of environmental factors in the development of the adrenergic phenotype. First, the activity of the quail TH gene promoter was analyzed in immortalized quail NC cells by transient transfection assay. We found that chick embryo extract (CEE), which is known to trigger adrenergic differentiation of NC cells in vitro, strongly enhanced reporter gene transcription. A sequence of only 77 nucleotides, including a cAMP-responsive element, was sufficient to elicit this response. Implication of cAMP in the CEE effect was further supported by the fact that CEE produced a stimulation of adenylate cyclase activity that was sensitive to beta-adrenoreceptor antagonists. Moreover, stimulation of TH gene expression by CEE could be reduced by beta-adrenergic antagonists or CA-depleted extract. We have subsequently investigated the possibility that TH expression during differentiation of nontransformed NC cells could also be influenced by CA via the cAMP pathway. In dissociated cultures of 3-day-old quail sclerotomes and of 2-day-old quail trunk NC, differentiation of TH+ cells was induced in the presence of forskolin, an activator of adenylate cyclase, and modulated by beta-adrenoreceptor ligands. In particular, the adrenergic-promoting effect of 10% CEE on trunk NC cultures was inhibited by beta-adrenoreceptor antagonists or by eliminating CA from the extract. In conclusion, these data suggest that CA (through activation of beta-adrenergic receptors and cAMP production) can stimulate the initial expression of TH in cultured NC cells and enhance TH transcription in immortalized NC cells. This supports the notion that exogenous CA, which is present in the early embryo, may promote the differentiation of sympathoadrenal precursors in vivo by stimulating TH gene activity.
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PMID:Regulation of the quail tyrosine hydroxylase gene in neural crest cells by cAMP and beta-adrenergic ligands. 810 92

We have studied the role of second messenger and protein phosphorylation pathways in mediating changes in neuronal function associated with opiate addiction in the rat locus coeruleus. We have found that chronic opiates increase levels of the G-protein subunits Gi alpha and Go alpha, adenylate cyclase, cyclic AMP-dependent protein kinase, and a number of phosphoproteins (including tyrosine hydroxylase) in this brain region. Electrophysiological data have provided direct support for the view that this up-regulation of the cyclic AMP system contributes to opiate tolerance, dependence, and withdrawal exhibited by these neurons. As the adaptations in G-proteins and the cyclic AMP system appear to occur at least in part at the level of gene expression, current efforts are aimed at identifying the mechanisms, at the molecular level, by which opiates regulate the expression of these intracellular messenger proteins in the locus coeruleus. These studies will lead to an improved understanding of the biochemical basis of opiate addiction.
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PMID:Second messenger and protein phosphorylation mechanisms underlying opiate addiction: studies in the rat locus coeruleus. 838 77

The occurrence, distribution and coexistence pattern of an array of neuropeptides and tyrosine hydroxylase in the human larynx, trachea, bronchi and lungs were studied by immunocytochemistry. A rich supply of nerve fibers containing vasoactive intestinal peptide (VIP) was seen close to blood vessels, glands and nonvascular smooth muscle. Pituitary adenylate cyclase-activating peptide (PACAP)-containing fibers were numerous among bundles of smooth muscle. Moderate numbers of helospectin-containing nerve fibers were seen in the nonvascular smooth muscle. The majority of neuropeptide Y (NPY)-containing fibers were located in the nonvascular smooth muscle; some fibers also occurred around blood vessels and glands. Substance P (SP) and calcitonin gene-related peptide (CGRP)-containing fibers were generally few and distributed beneath the epithelium, among bundles of smooth muscle, around blood vessels and glands. A conspicuous finding was the lack of SP- and CGRP-containing fibers within the respiratory epithelium. Galanin-containing nerve fibers were moderate in number among bundles of smooth muscle. Tyrosine hydroxylase-containing fibers were numerous around blood vessels and glands. The majority of the VIP-containing nerve fibers present in nonvascular smooth muscle also stored PACAP and helospectin. A subpopulation of VIP-containing fibers in both vascular and nonvascular smooth muscle and around glands stored NPY. Additionally, galanin was found to occur in many VIP-containing fibers located among bundles of smooth muscle.
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PMID:Peptide-containing nerve fibers in human airways: distribution and coexistence pattern. 849 74

In previous studies, we demonstrated that tyrosine hydroxylase and neurofilament proteins are regulated by chronic morphine and chronic cocaine treatments in the ventral tegmental area in Sprague-Dawley rats and that the inbred Lewis and Fischer 344 rat strains, under drug-naive conditions, show different levels of these proteins specifically in this brain region. In the current study, we compared Lewis and Fischer rats with respect to levels of adenylate cyclase, cyclic AMP-dependent protein kinase and G-proteins in the nucleus accumbens (NAc) and locus coeruleus (LC), brain regions in Sprague-Dawley rats where these proteins are regulated by chronic exposure to morphine or to cocaine. We found that levels of adenylate cyclase and cyclic AMP-dependent protein kinase activity are higher in the NAc and LC of Lewis rats compared to Fischer rats, whereas levels of Gi alpha and G beta were lower. These strain differences were not seen in several other brain regions analyzed and no strain differences were detected in levels of other G-protein subunits. Lewis and Fischer rats also differed in the ability of chronic morphine to regulate adenylate cyclase and cyclic AMP-dependent protein kinase in the NAc and LC. In the NAc, chronic morphine increased levels of the two enzymes in the Fischer strain only, whereas in the LC chronic morphine increased levels of the enzymes in both strains, with more robust effects seen in the Lewis rat. To understand possible physiological consequences of these strain differences in the cyclic AMP pathway, we studied LC neuronal activity under basal and chronic morphine-treated conditions. LC neurons of Lewis rats showed higher spontaneous firing rates in brain slices in vitro than those of Fischer rats and also showed greater morphine-induced increases in responsiveness to bath-applied 8-bromo-cyclic AMP. These electrophysiological findings are generally consistent with the biochemical observations. Moreover, Lewis and Fischer rats displayed very different opiate withdrawal syndromes, with different types of behaviors elicited upon precipitation of opiate withdrawal with the opiate receptor antagonist, naltrexone. The possible relationship between these behavioral findings and the biochemical and electrophysiological data is discussed. These studies provide further support for the possibility that Lewis and Fischer rat strains provide a useful model system in which some of the genetic factors that contribute to drug-related behaviors can be investigated.
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PMID:Lewis and Fischer rat strains display differences in biochemical, electrophysiological and behavioral parameters: studies in the nucleus accumbens and locus coeruleus of drug naive and morphine-treated animals. 851 51

The effect of pituitary adenylate cyclase-activating polypeptide1-38 (PACAP1-38) on the synthesis of dopamine in cultured bovine adrenal chromaffin cells was examined. PACAP1-38 stimulated [14C]dopamine synthesis from [14C]tyrosine, in a concentration-dependent manner, causing maximal stimulation at 10(-7)M. This stimulatory action of PACAP1-38 was not significantly inhibited by staurosporine (an inhibitor of protein kinase C) or in the cells in which protein kinase C was down-regulated by prolonged exposure to TPA (an activator of protein kinase C), whereas it was partially attenuated in Ca(2+)-free medium. PACAP1-38 increased the formation of [3H] inositol phosphates, [Ca2+]i, 45Ca2+ uptake and cAMP level. The peptide also stimulated the phosphorylation of tyrosine hydroxylase, the enzyme catalyzing the rate-limiting step in dopamine synthesis. Dopamine synthesis and tyrosine hydroxylase phosphorylation stimulated by the maximal effective concentration of dibutyryl cAMP or high K+, which activates Ca2+ uptake, were further enhanced by PACAP1-38. These results indicated that PACAP1-38 may stimulate the activities of cAMP- and calcium-dependent protein kinases in cultured bovine adrenal chromaffin cells, resulting in increase in the synthesis of dopamine probably by stimulation of phosphorylation of tyrosine hydroxylase.
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PMID:Pituitary adenylate cyclase-activating polypeptide stimulates the synthesis of dopamine in cultured bovine adrenal chromaffin cells. 852 52

Previous studies [Czyzyk-Krzeska et al.: J Neurochem 1992;58:1538] demonstrated the relationship between low O2 breathing and tyrosine hydroxylase (TH) gene expression in chemosensory type I cells of the carotid body. In the present study, we have exposed carotid bodies in vitro to hypoxic superfusion media, and subsequently used the reverse transcriptase-polymerase chain reaction technique to measure relative changes in the TH transcript in an effort to elucidate the cellular mechanisms which regulate TH gene expression. Carotid bodies and superior cervical ganglia (SCG) were exposed for 3 h to superfusion media equilibrated with either 10% O2 or 100% O2 and then rapidly frozen on dry ice prior to extraction of total RNA. Hypoxia elevated TH mRNA in the carotid body 3.63 +/- 0.84-fold (mean +/- SEM), while in contrast, these parameters were unchanged in SCG similarly exposed to hypoxic media. Incubation of carotid bodies in zero Ca2+ superfusates greatly attenuated the increase in TH mRNA evoked by hypoxia (1.39 +/- 0.34-fold increase; p < 0.025 compared to normal Ca2+ group). Likewise, exposure to the guanylate cyclase activator, atriopeptin III (100 nM), attenuated the TH mRNA hypoxic response (p < 0.005), while activation of adenylate cyclase with forskolin (10 microM) tended to elevate the response to low O2. Our data suggest that hypoxia, independent of circulating hormones, induces TH gene expression in the carotid body, and that multiple factors, including [Ca2+] and cyclic nucleotides, may be important components of the signal transduction pathway.
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PMID:Second messenger regulation of tyrosine hydroxylase gene expression in rat carotid body. 870 28


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