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

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous studies, cystic fibrosis (CF) fibroblasts were demonstrated to be resistant to the cytotoxic effects of ouabain, dexamethasone, and the sex hormones, dihydrotestosterone, 17beta-estradiol, and progesterone. We now show that CF fibroblasts also exhibit greatly increased resistance to the cytotoxic effects of exogenous dibutyryl cyclic AMP (cAMP), as well as to isoproterenol and theophylline, drugs which are known to increase endogenous levels of cAMP. CF cells were also shown to have normal amounts of (3H)cAMP binding to protein kinase as well as normal amounts of cAMP-stimulated protein kinase activity. Phosphodiesterase in CF cells was also found to be stimulated by cAMP to the same degree as in normal cells. These findings suggest that there is no detectable protein kinase deficiency in CF cells. cf cells thus appear to be unlike some cAMP-resistant mutants described by others which are defective in protein kinase activity and cAMP regulation of phosphodiesterase levels. The cross-resistance of CF fibroblasts to ouabain, steroid hormones, and cAMP may provide a unique opportunity to study the biochemical events involved in the metabolism of these drugs as well as the basic biochemical defect in a common human genetic disease.
...
PMID:Pleiotropic drug resistance in cystic fibrosis fibroblasts: increased resistance to cyclic AMP. 21 May 26

We established a pancreatic adenocarcinoma cell line (CFPAC-1) from a patient with cystic fibrosis (CF) and assessed some of its properties. The cells show epithelial morphology and express cytokeratin and oncofetal antigens characteristic of pancreatic duct cells. Basal and stimulated levels of cAMP and cAMP-dependent protein kinase and the biophysical properties of single Cl- channels in CFPAC-1 are similar to those of airway and sweat gland primary cultures and Cl(-)-secreting epithelial cell lines. Anion transport and single Cl- channel activity was stimulated by Ca2+ ionophores but not by forskolin, cAMP analogs, or phosphodiesterase inhibitors. The cells express the CF gene and manifest the most common CF mutation, deletion of three nucleotides resulting in a phenylalanine-508 deletion. These properties have been stable through greater than 80 passages (24 months), suggesting that CFPAC-1 can serve as a continuous cell line that displays the CF defect.
...
PMID:A cystic fibrosis pancreatic adenocarcinoma cell line. 169 30

1. Isolated coiled reabsorptive sweat ducts from normal subjects and patients with cystic fibrosis (CF) were cultured in vitro. Cells were harvested and plated onto permeable supports to form confluent cell sheets. The Ussing chamber technique was used to study pharmacological regulation of the transepithelial ion transport in these membranes. 2. Addition of a stable cyclic AMP analogue, 8-Br-cyclic AMP, to normal cell cultures resulted in a decrease of the transepithelial potential difference (PD). 3. Forskolin exposure resulted in a similar PD decrease, which was augmented by the phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX). 4. Exposure to isoprenaline, prostaglandin E2 (PGE2), and phenylephrine resulted in a response mimicking the forskolin-induced response, that was also amplified by IBMX. 5. Pre-incubation with cholera toxin abolished the isoprenaline response and reduced the control resistance. 6. Propranolol abolished the responses induced by isoprenaline and phenylephrine, whereas phentolamine had no effect. PGE2-induced responses were inert to both types of blockers. 7. Indomethazine addition to an unstimulated membrane resulted in a weak PD increase, i.e. a response opposite to that induced by isoprenaline. 8. IBMX addition to an unstimulated membrane resulted in a weak isoprenaline-like response. When the cells were pre-treated with indomethazine this IBMX response was absent. 9. Unidirectional Cl- isotope flux studies demonstrated a large increase of net Cl- reabsorption in response to isoprenaline and PGE2. 10. Mannitol isotope flux studies revealed that the paracellular permeability was unaffected by isoprenaline exposure. 11. Membranes derived from CF patients did not respond similarly to any of these agents. However, a weak spike, occasionally followed by a gradual increase of the short-circuit current (Iscc), was observed in both normal subjects and CF patients. 12. It is concluded that the primary effect on ion transport of factors increasing the cyclic AMP in normal cultured sweat duct cells is an activation of a transcellular Cl- permeability. This effect was missing in cells derived from CF patients.
...
PMID:Chloride permeability regulation via a cyclic AMP pathway in cultured human sweat duct cells. 169 99

Adrenergic secretory responses of submandibular glands from control subjects and cystic fibrosis patients have been studied in vitro. In control tissues, isoproterenol (10 mumol/l) and noradrenaline (10 mumol/l) increased release of mucins and amylase to a similar extent (approximately 3-fold) and their actions were mediated by stimulation of beta-adrenergic receptors. In cystic fibrosis tissues, isoproterenol did not significantly increase release of mucins or amylase above the basal rate during 40 min incubation, whereas secretion in response to noradrenaline was not significantly different from that in control tissues. In the presence of a phosphodiesterase inhibitor, secretion of mucins and amylase in response to isoproterenol (10 mumol/l) in cystic fibrosis tissues was increased to the same level as that of noradrenaline (10 mumol/l); giving the same pattern of adrenergic responses in cystic fibrosis tissues as in control. The results suggest that overactivity of phosphodiesterase in cystic fibrosis cells might be the cause of the observed decreased secretion in response to a beta-adrenergic agonist.
...
PMID:Adrenergic secretory responses of submandibular tissues from control subjects and cystic fibrosis patients. 241 33

Labial glands from patients with cystic fibrosis (CF) were tested for a disease-related decrease in cholinergically-induced K release. Labial gland slices from normal controls and patients with cystic fibrosis were incubated in vitro in the presence or absence of cholinergic and adrenergic agonists and with or without a phosphodiesterase inhibitor. Both control and CF glands released K in response to cholinergic stimulation only; no K release response was detected to alpha- or beta- adrenergic stimulation. In contrast to previous results reported for parotid glands, no CF-related decrease in cholinergically-induced K release was detected. Both normal and CF glands released significantly less K with carbachol stimulation in the presence of the phosphodiesterase inhibitor. Overall, the results suggest considerable interglandular differences in disease sensitivity and functional regulation of K release.
...
PMID:Potassium release in labial glands from controls and patients with cystic fibrosis. 246 34

Human lymphocyte and granulocyte membranes contain an enzyme, phosphatidylethanolamine N-methyltransferase (PEMT), which catalyzes the transfer of a methyl group from S-adenosylmethionine to the polar head group of phosphatidylethanolamine to form phosphatidylmonomethylethanolamine. This enzyme, in lymphocyte membranes, has Km for S-adenosylmethionine of 7.01 +/- 2.9 (SD) microM, and specific activity 0.57 +/- 0.31 pmol/mg protein/15 min, is inhibited by S-adenosylhomocysteine, displays optimal activity at pH 8.0-9.0, and is stimulated by isoproterenol in dose-dependent, propranolol-inhibitable fashion, to a lesser extent by epinephrine, but not by norepinephrine, prostaglandin E1, concanavalin A, or adenosine 3':5' cyclic monophosphate, with or without phosphodiesterase inhibitors. Granulocyte membrane PEMT has Km for S-adenosylmethionine of 4.4 microM and specific activity 0.54 +/- 0.51 pmol/mg protein/15 min, is inhibited by S-adenosylhomocysteine, displays optimal activity at pH 8.0-9.5, and is stimulated by isoproterenol greater than epinephrine greater than norepinephrine, but not by prostaglandin E1, serum-treated zymosan, formyl-methionyl-leucyl-phenylalanine, or adenosine 3':5' cyclic monophosphate. Because activation of PEMT reportedly contributes to several processes known to be abnormal in cystic fibrosis, including coupling of the beta-adrenergic receptor to adenylate cyclase, activity of PEMT was compared in lymphocyte and granulocyte membrane preparations from cystic fibrosis patients and healthy controls, in which abnormal coupling of beta-adrenergic receptor to adenylate cyclase had been demonstrated. For both cell types, the Km and specific activity of PEMT were comparable in normal and cystic fibrosis samples. Therefore, the hypothesis that reduced PEMT activity accounts for the impaired coupling of beta-adrenergic receptor to adenylate cyclase in lymphocytes and granulocytes in cystic fibrosis is rejected.
...
PMID:Lymphocyte and granulocyte phosphatidylethanolamine N-methyltransferase: properties and activity in cystic fibrosis. 302 2

Activities of the microvillar enzymes gamma-glutamyltranspeptidase (GGTP), aminopeptidase M (APM), phosphodiesterase and maltase have been examined in second-trimester amniotic fluid as possible aids to the early prenatal diagnosis of cystic fibrosis (CF). The two peptidases, GGTP and APM, gave best results. If the fifth percentile of the normal range is used as an action line, the sensitivity of a positive test (low GGTP value) is 78% and the predictability 84%. At the tenth percentile the sensitivity is 100% and the predictability 77%. These approximate figures apply only to pregnancies where there has been a previous affected child. Until the primary protein defect in CF is discovered, this may prove an acceptable form of prenatal diagnosis to the high-risk mother.
...
PMID:Prenatal diagnosis of cystic fibrosis by assay of amniotic fluid microvillar enzymes. 614 94

Thirteen cystic fibrosis and 12 normal strains of skin fibroblasts obtained from the Institute for Medical Research were compared for their degree of production of cyclic adenosine 3':5'-monophosphate in response to isoproterenol and prostaglandin E1. There were no significant differences in their quantitative responses in content of cyclic AMP at two different times whether these cells were growing exponentially or were already confluent. All strains responded similarly to the presence of two types of phosphodiesterase inhibitor. The averaged initial rates of the response to isoproterenol in exponentially growing cells were also similar for the two sets of strains. Although response differed greatly between strains, the response of each strain was relatively reproducible.
...
PMID:Cystic fibrosis fibroblasts respond normally to isoproterenol. 617 Sep 25

It has been proposed that a combination of an activated adenylyl cyclase and a high concentration of a phosphodiesterase inhibitor (isobutylmethylxanthine [IBMX], 5 mM) stimulates Cl- secretion mediated by the heterologously expressed cystic fibrosis transmembrane regulator protein carrying the most common cystic fibrosis (CF) mutation (delta F508). We tested whether Cl- secretion could be stimulated by this protocol in vitro and in vivo in CF airway epithelia expressing endogenous delta F508 CFTR protein. In cultured airway preparations, forskolin (a direct adenylyl cyclase activator) stimulated Cl- secretion in amiloride-pretreated normal (delta Isc = 7.1 +/- 1.7 microA.cm-2) but not CF tissues (delta Isc = -02 +/- 0.1 microA.cm-2). Unexpectedly, IBMX partially inhibited the forskolin-induced Cl- secretion in normal tissues; IBMX addition had no effect on CF tissues. Direct measurements of cell cAMP concentrations revealed that 0.1 mM IBMX and forskolin produced the maximum levels of cell cAMP levels attainable with this drug combination, and 5 mM IBMX was without further effect. The combination of forskolin (10(-5) M) and isoproterenol, an adenylyl cyclase activator (10(-5) M), produced approximately 3 times higher levels of cAMP than forskolin/IBMX but also did not induce Cl- secretion in CF tissues. Studies of Cl- secretion in vivo, assessed by the transepithelial electric potential difference (PD), showed that isoproterenol (10(-5) M) stimulated Cl- secretion (delta PD = -16.3 +/- 4.3 mV; n = 4) in nasal epithelia of normal subjects but not in CF patients homozygous for the delta F508 mutation (delta PD = -2.6 +/- 1.9 mV; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Isobutylmethylxanthine fails to stimulate chloride secretion in cystic fibrosis airway epithelia. 768 24

Airway epithelial cells bearing mutations of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) possess an increased Na+ conductance along with their well described defect of cAMP dependent Cl- conductance. Currently it is not clear, how this occurs, and whether it is due to a CFTR control of epithelial Na+ conductances which might be defective in CF patients. In the present study, we have tried to identify possible interactions between both CFTR and the epithelial Na+ conductance by overexpressing respective cRNAs in Xenopus oocytes. The expression of all three (alpha, beta, gamma) subunits of the rat epithelial Na+ channel (rENaC) and wild type (wt) CFTR resulted in the expected amiloride sensitive Na+ and IBMX (1 mmol/l) activated Cl- currents, respectively. The amiloride sensitive Na+ conductance was, however, inhibited when the wt-CFTR Cl- conductance was activated by phosphodiesterase inhibition (IBMX). In contrast, IBMX had no such effect in deltaF508 and Na+ channels coexpressing oocytes. These results suggest that wt-CFTR, but not deltaF508-CFTR, is a cAMP dependent downregulator of epithelial Na+ channels. This may explain the higher Na+ conductance observed in airway epithelial cells of CF patients.
...
PMID:Wild type but not deltaF508 CFTR inhibits Na+ conductance when coexpressed in Xenopus oocytes. 864 37


1 2 3 4 5 Next >>

---