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PubMed2005

Health-related quality of life improves in children and adolescents with inflammatory bowel disease after attending a camp sponsored by the Crohn's and Colitis Foundation of America.

PURPOSE: To describe the reported health-related quality of life (HRQOL) in children and adolescents with inflammatory bowel disease (IBD) after attending an IBD summer camp. METHODS: A prospective analysis of quality of life was completed at an overnight camp that was exclusively for patients with IBD, which was sponsored by the Crohn's and Colitis Foundation of America. The IMPACT-II questionnaire (Canada and United States) and the State-Trait Anxiety Inventory for Children were administered to the campers at the beginning and at the end of a 1-week camp to assess HRQOL and anxiety. The IMPACT-II questionnaire consists of 35 questions measuring 6 quality-of-life domains (i.e., bowel domain, systemic symptoms, emotional functioning, social functioning, body image, and treatment/interventions). The State-Trait Anxiety Inventory for Children consists of 2 different 20-item sets of questions. One set assesses state anxiety, and the other, trait anxiety. A repeated-measures multivariate analysis of variance was performed to determine the differences between scores attained before and after camp on the IMPACT-II questionnaire and in each of its domains. Paired sample t tests were performed on state and trait anxiety before and after camp. RESULTS: A total of 125 individuals consented to participate, but 61 patients (50 girls and 11 boys; age range, 9 to 16 y) completed the IMPACT-II questionnaire in full. Of those 61 patients, 47 had Crohn's disease and 14 had ulcerative colitis. There was statistically significant improvement between the mean (+/-SD) precamp total score (172.95 +/- 36.61) and the mean postcamp total score (178.71 +/- 40.97; P = 0.035), bowel symptoms scores (P = 0.036), social functioning scores (P = 0.022), and treatment interventions scores (P = 0.012). No difference was found between anxiety scores before and after camp on either the state or trait anxiety inventories (n = 55; P > 0.05). CONCLUSIONS: Overall, HRQOL improved in children after attending IBD summer camp. This exploratory study suggests that contributing factors for these improvements may be an increase in social functioning, a better acceptance of IBD symptoms, and less distress regarding treatment interventions, suggesting that a camp that is specifically designed for children with IBD may normalize the chronic illness experience. However, future research using a multimodal measurement approach is warranted to support these conclusions.

Adolescent↗
PubMedDate not supplied

Self-esteem measurement before and after summer burn camp in pediatric burn patients.

Pediatric burn injury results in significant mortality and morbidity, from which some children will experience prolonged psychological and social difficulty. As early as 1967, it was noted that participation in a group was important in the resolution of problems caused by severe disability and stressful experiences. Since 1982, there have been summer burn camps for children and adolescent burn survivors. The primary focus of camp is to have "fun" at the various daily activities. The principal goal, however, is psychosocial readjustment. Fifty-three burn survivors attended the 1-week duration annual summer camp. Campers were invited to complete a Rosenberg Self-Esteem Scale on the first day of summer burn camp and shortly after the camp ended. Younger children were assisted with the survey tool by their parents. Of the 53 campers, 45 completed both pre- and postcamp surveys. The age of the campers ranged from 6 to 18 years (mean, 12.8 years). Burn size ranged from 1% to 90% TBSA (mean, 30.4% TBSA). The interval from date of injury to camp attendance was 2 months to 15.5 years. Nine campers had never attended burn camp before this year. Twenty- nine percent of the campers had an increase in self-esteem score. Fifty-eight percent had no change, and 13% demonstrated a decrease. The burn camp experience though an enriching summer activity, did not necessarily increase self-esteem in the majority of campers as measured by the survey tool employed.

Adolescent↗
PubMed2003

Summer camps and quality of life in children and adolescents with type 1 diabetes.

Topics concerning quality of life in children and adolescents with Type 1 Diabetes Mellitus (T1DM) and summer camps, have only recently appeared in the scientific literature. Interest in quality of life in diabetic patients has lately increased. The Hvidore study group has recruited 2000 patients from several countries and has published an important paper whose conclusions suggest that T1DM patients have a better quality of life if they have a good metabolic control. The aim of this paper is to evaluate if summer camps, seen as an educational and therapeutic tool, can improve quality of life by increasing knowledge and self-management capacities. Certainly summer camps help T1DM children and adolescents to understand that they can be on vacations, practice sports, have fun with other children away from home and parents, just like every other child and adolescent. At summer camps T1DM patients become aware of not being the only ones to deal with the problem of diabetes; in addition parents become aware of their child's skills in the disease management and lastly improve the relationship with the medical staff who will have the opportunity of living an extremely important training experience. The more ambitious aim of summer camps, i.e. the gaining of knowledge and self-management skills and improvement in metabolic control, seems difficult to achieve. The limited literature available suggests that it is unlikely that one or more summer camps will contribute to the improvement of metabolic control; nevertheless, it is not easy to make such evaluations with scientific criteria. We think that Italian guidelines for summer camps should help in standardizing the organization and management; in this way it will be probably easier to evaluate the impact of summer camps on the quality of life.

Adolescent↗
PubMed2004

Lack of evidence of transmission of Pseudomonas aeruginosa among cystic fibrosis patients attending health camps at the Dead Sea, Israel.

BACKGROUND: Transmission of Pseudomonas aeruginosa among cystic fibrosis patients attending health camps has been reported previously. OBJECTIVES: To determine the transmission of P. aeruginosa among CF patients during three winter camps in the Dead Sea region in southern Israel. METHODS: Three consecutive CF patient groups were studied, each of which spent 3 weeks at the camp. The patients were segragated prior to camp attendance: patients who were not colonized with P. aeruginosa constituted the first group, and colonized patients made up the two additional groups. Sputum cultures were obtained upon arrival, at mid-camp and on the last day. Environmental cultures were also obtained. Patients were separated during social activities and were requested to avoid social mingling. Isolates were analyzed by antibiotic susceptibility profile and by pulsed field gel electrophoresis. RESULTS: Ninety isolates from 19 patients produced 28 different fingerprint patterns by PFGE. Isolates from two siblings and two patients from the same clinic displayed the same fingerprint pattern. These patients were already colonized with these organisms upon arrival. Two couples were formed during the camp, but PFGE showed no transmission of organisms. All other patients' isolates displayed unique fingerprint patterns and were distinguishable from those of other attendees, and none of the P. aeruginosa-negative patients acquired P. aeruginosa during camp attendance. Environmental cultures were negative for P. aeruginosa. CONCLUSIONS: We were unable to demonstrate cross-infection of P. aeruginosa among CF patients participating in health camps at the Dead Sea who were meticulously segregated.

Adolescent↗
PubMed1980

A residential camp experience as an approach to adolescent weight management.

A five day weight management camp for adolescents is described. Three components of weight management comprise of the camp's educational basis: 1) Nutrition Education, 2) Behavior Modeling, and 3) Physical Activity. Program planning and organizational methods are described. Thirty-five teenagers, age 13-17, attended the program. The mean weight loss for camp participants, measured at six months after camp, was 3.3 pounds. Triceps skinfold measurements showed an average decrease of 3.6mm after three months. The Wahler Self-Description Inventory was administered to measure favorable and unfavorable attributes through a self-evaluation process. Results showed a steady and continuous increase in favorable scores through the course of the camp and at the time of follow-up. Unfavorable scores were high prior to camp, followed by a sudden drop in unfavorable scores after the week of supportive therapy, followed by a leaving off effect of the 3-month follow-up session. A program evaluation by camp participants revealed that the residential camp environment was a useful approach to adolescent weight management therapy.

Adolescent↗
PubMed1995

The impact of a summer asthma camp experience on asthma education and morbidity in children.

BACKGROUND: This study examines whether an educational program emphasizing self-management skills can be successfully implemented in an asthma camp setting, and the degree to which this camp experience would affect asthma-associated morbidity among children attending such a program. METHODS: Ninety asthmatic children between the ages of 6 and 12 years who were attending a summer asthma camp were enrolled in the study. A precamp questionnaire was sent to the parents of these children to assess asthma morbidity during the preceding 12 months and to determine the prevalence of the use of peak flow meters and spacer devices by their children. At camp, children received educational sessions on asthma self-management, including training in the proper use of spacer devices and peak flow meters. Follow-up questionnaires were sent to the parents at 1 and 6 months after camp to assess the use of these devices and to measure subsequent asthma morbidity. RESULTS: Precamp use of spacer devices among all participants was 51.9%; the 1-month and 6-month post-camp use of spacer devices significantly increased to 92.4% (P < .001) and 85.9% (P < .001), respectively. The precamp use of peak flow meters was 50.0%; the 1-month and 6-month postcamp use was increased to 95.0% (P < .001) and 87.7% (P < .001), respectively. Six-month follow-up revealed a significant decrease in urgent outpatient visits for asthma exacerbations and a significant decrease in school day absences due to asthma. CONCLUSIONS: An asthma camp is an effective environment for a patient education program emphasizing self-management skills. Children with moderate to severe asthma who attend such a camp may experience a decrease in subsequent asthma-associated morbidity.

Ambulatory Care↗
PubMed1993

Role of cAMP in regulating cytotoxic T lymphocyte adhesion and motility.

We investigated the functional role of the cAMP pathway in human cytotoxic T lymphocyte (CTL)-target interaction. Pharmacological increase of intracellular cAMP concentration ([cAMP]i) inhibits killing, especially at low effector-to-target ratios, suggesting an inhibitory effect on CTL recycling. We show that this inhibitory effect is primarily at the level of conjugate formation. Pharmacological increase in [cAMP]i, as well as treatment with cytochalasin D, results in a "rounding up" of the CTL and inhibition of the dramatic changes in shape that occur when a CTL forms a conjugate, even with an irrelevant target. In addition, pharmacological increase in [cAMP]i affects the cytoskeleton of the CTL since it induces a decrease of filamentous actin, as detected by flow cytometry on phalloidin-stained CTL, and a stabilization of microtubules, as detected by increased resistance to the disrupting action of nocodazole. In mature CTL (but not in their immature precursors), T cell receptor triggering by specific targets results in a measurable increase in cAMP levels and strongly synergizes with adenylyl cyclase activators such as prostaglandin E2, cholera toxin and forskolin. We suggest that T cell receptor triggering may induce accumulation of cAMP that interferes with cytoskeleton function and, thus, terminates CTL secretion and adhesion. These effects of cAMP are rapidly reversible and may regulate CTL recycling.

Actins↗
PubMed2004

Tumor necrosis factor reduces cAMP production in rat microglia.

cAMP has been reported to exert a neuroprotective role in several in vivo and in vitro models of brain pathologies, mainly by regulating microglial activation and orienting these cells toward a neuroprotective phenotype. In order to elucidate the intracellular pathways regulated by tumor necrosis factor (TNF) in glial cells, I have studied the modulation of cAMP accumulation by TNF in microglia and astrocyte cultures obtained from the neonatal rat brain. Pre-treatment of microglia with TNF reduced in a dose- and time-dependent manner cAMP accumulation induced by forskolin (FSK), in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX). The TNF inhibitory action was 90% reverted by a neutralizing polyclonal anti-TNF antibody and was not prevented by a 16 h pre-treatment of microglial cultures with the Gi protein inhibitor pertussis toxin (PTx). These results suggest that TNF acts at a step of the cAMP transduction pathway other than receptors, G proteins, and phosphodiesterases. The target of TNF appeared to be adenylyl cyclase, whose ability to synthesize cAMP was markedly reduced (up to 50%) in membranes prepared from TNF-treated microglial cells, both in basal conditions and after stimulation with FSK. TNF induced a time-dependent degradation of IkappaB-alpha in microglial cells that was reverted by two inhibitors of nuclear factor kappaB activation, N-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and N-CBZ-Leu-Leu-Leu-al (MG132). The same inhibitors also markedly prevented the reduction of FSK-evoked cAMP accumulation by TNF, suggesting the involvement of NFkappaB in the regulation of adenylyl cyclase by TNF in microglia. Conversely, cAMP accumulation in astrocytes was not affected by TNF. Based on these findings, it is proposed that the ability of TNF to inhibit cAMP synthesis in microglia may exacerbate its response and contribute to cell damage in neuroinflammation and neurodegeneration, possibly through enhanced release of proinflammatory and/or cytotoxic factors.

Adenylyl Cyclases↗
PubMed2006

Insulin-like growth factor binding protein-4 (IGFBP-4) is a novel anti-angiogenic and anti-tumorigenic mediator secreted by dibutyryl cyclic AMP (dB-cAMP)-differentiated glioblastoma cells.

cAMP has been shown to reverse the transformed phenotype of various cancer cells. Human glioblastoma U87MG cells exposed to 500 microM dB-cAMP for 6 days showed reduced proliferation, attenuated invasiveness, and inability to induce angiogenic responses in human brain endothelial cells (HBECs) grown in Matrigeltrade mark. VEGF was the principal mediator of angiogenic actions of U87MG conditioned media (CM), since VEGF neutralizing antibody completely inhibited U87MG-induced angiogenic responses and no detectable levels of IGF, bFGF, and PlGF were found in U87MG CM. VEGF release was induced ( approximately 20%) in dB-cAMP-treated U87MG cells, suggesting a simultaneous induction of anti-angiogenic mediators. Down-stream effectors of dB-cAMP actions in U87MG were investigated by microarray gene expression analysis. Detected increases in differentiation genes, staniocalcin-1 and Wnt-5a, and angiogenesis-related genes, PAI-1, SPARC, IGFBP-4, IGFBP-7, PAPP-A, and PRSS-11 in dB-cAMP-treated U87MG cells were validated by real-time PCR, Western blot, and/or ELISA. A subsequent series of experiments identified IGFBP-4 as the principal anti-angiogenic mediator secreted by glioblastoma cells in response to dB-cAMP. Human recombinant IGFBP-4 inhibited the angiogenic response of HBEC induced by U87MG CM, whereas anti-human IGFBP-4 antibody restored the pro-angiogenic activity of dB-cAMP-treated U87MG CM. Since neither U87MG nor HBEC cells secreted detectable levels of IGF-I, and there are no known cellular IGFBP-4 receptors, the anti-angiogenic effect of IGFBP-4 was likely IGF-I-independent and indirect. IGFBP-4 also antagonized angiogenic effects of VEGF(165), PlGF, and bFGF, and reduced U87MG colony formation in soft-agar. IGFBP-4 is a novel dB-cAMP-induced anti-angiogenic and anti-tumorigenic mediator that may be a promising candidate for glioblastoma therapy.

Antineoplastic Agents↗
PubMed1988

Major 56,000-dalton, soluble phosphoprotein present in bovine sperm is the regulatory subunit of a type II cAMP-dependent protein kinase.

It has been shown that cAMP-dependent phosphorylation of a soluble sperm protein is important for the initiation of flagellar motion. The suggestion has been made that this motility initiation protein, named axokinin, is the major 56,000-dalton phosphoprotein present in both dog sperm and in other cells containing axokinin-like activity. Since the regulatory subunit of a type II cAMP-dependent protein kinase is a ubiquitous cAMP-dependent phosphoprotein of similar subunit molecular weight as reported for axokinin, we have addressed the question of how many soluble 56,000-dalton cAMP-dependent phosphoproteins are present in mammalian sperm. We report that in bovine sperm cytosol, the ratio of the type I to type II cAMP-dependent protein kinase is approximately 1:1. The type II regulatory subunit is related to the non-neural form of the enzyme and undergoes a phosphorylation-dependent electrophoretic mobility shift. The apparent subunit molecular weights of the phospho and dephospho forms are 56,000 and 54,000 daltons, respectively. When bovine sperm cytosol or detergent extracts are phosphorylated in the presence of catalytic subunits, two major proteins are phosphorylated and have subunit molecular weights of 56,000 and 40,000 daltons. If, however, the type II regulatory subunit (RII) is quantitatively removed from these extracts using either immobilized cAMP or an anti-RII monoclonal affinity column, the ability to phosphorylate the 56,000- but not 40,000-dalton polypeptide is lost. These data suggest that the major 56,000 dalton cAMP-dependent phosphoprotein present in bovine sperm is the regulatory subunit of a type II cAMP-dependent protein kinase and not the motility initiator protein, axokinin.

Animals↗
PubMed1990

Growth and protein phosphorylation in the Nb2 lymphoma: effect of prolactin, cAMP, and agents that activate adenylate cyclase.

The Nb2 T lymphoma is unique in that these lymphocytes proliferate in response to prolactin as well as in response to interleukin-2. In this study, we have examined the responsiveness of the adenylate cyclase system in Nb2 cells and the role of this signaling system in regulating proliferation and protein phosphorylation. An analog of cAMP inhibited prolactin-stimulated proliferation and blocked a prolactin-induced decrease in protein phosphorylation. Forskolin, a potent activator of adenylate cyclase in T lymphocytes, did not elevate cAMP levels in Nb2 cells and was not an effective inhibitor of prolactin-induced proliferation. In fact, one preparation of forskolin stimulated proliferation of quiescent Nb2 cells. Like forskolin, prostaglandin E2 did not stimulate cAMP production in Nb2 cells even though it increased cAMP in a preparation of rat peripheral blood lymphocytes. Cholera toxin appeared to ADP-ribosylate a stimulatory guanine nucleotide-binding protein in Nb2 cells, but the toxin did not increase intracellular levels of cAMP nor was it a potent anti-mitogenic agent. Pertussis toxin, an agent that can increase cAMP production through suppression of the inhibitory guanine nucleotide-binding protein, exerted only minor anti-proliferative actions on prolactin-stimulated Nb2 cells. These data suggest that cAMP inhibits Nb2 cell proliferation and prolactin-induced changes in protein phosphorylation but that the adenylate cyclase system in our clone of Nb2 cells responds poorly to agents that normally increase cAMP.

Adenylate Cyclase Toxin↗
PubMed1988

Bombesin enhancement of cAMP accumulation in Swiss 3T3 cells: evidence of a dual mechanism of action.

Addition of bombesin in the presence of either forskolin or cholera toxin caused a marked (4-6 fold) enhancement of cAMP accumulation in Swiss 3T3 cells. This effect was time and concentration dependent, induced by various bombesin-like peptides and blocked by a bombesin antagonist. Enhancement of cAMP accumulation by bombesin was diminished by chronic pretreatment with phorbol dibutyrate implicating the involvement of protein kinase C in the activation. Pretreatment with pertussis toxin, which uncouples protein kinase C activation from cAMP accumulation (Proc. Natl. Acad. Sci. U.S.A., 84:2282, 1987) also inhibited bombesin enhancement of cAMP. Bombesin was also shown to release E type prostaglandins into the medium, an effect which was abolished by the cyclooxygenase inhibitor indomethacin. Low concentrations (100 nM) of indomethacin partially inhibited the accumulation of cAMP by bombesin in the presence of forskolin indicating that the release of E type prostaglandins into the medium is also involved in the accumulation of cAMP by bombesin. The additive nature of PBt2-mediated down-regulation and treatment with indomethacin suggests that activation of protein kinase C and the release of E type prostaglandins provide two distinct pathways involved in the enhancement of cAMP accumulation by bombesin. Finally, bombesin in the presence of forskolin stimulated the phosphorylation of the intermediate filament component vimentin, identified in the accompanying paper as a substrate for a cAMP dependent protein kinase in intact Swiss 3T3 cells.

Animals↗
PubMed1994

Differential effects of cAMP-elevating drugs on stimulus-induced cytosolic calcium changes in human basophils.

Drugs that elevate cAMP levels in human basophils are known to inhibit immunoglobulin E (IgE)-mediated histamine release. We have examined whether cAMP-active agents inhibit the cytosolic Ca2+, [Ca2+]i, response that normally accompanies activation of basophils. As previously described, this [Ca2+]i response is biphasic, one phase dependent on internal sources of calcium and a second later phase dependent on extracellular calcium, as observed in many cell types. Forskolin and rolipram or their combination had no effect on the initial elevation of cytosolic calcium that follows stimulation with anti-IgE antibody. In contrast, the second phase of the IgE-mediated calcium response was inhibited by these agents. For IgE-mediated responses, the relative efficacy of various cAMP active agents (rolipram approximately forskolin < dibutyryl cAMP < forskolin + rolipram) for the inhibition of histamine release and the second-phase calcium response was similar and roughly paralleled the measured increase in basophil cAMP. In contrast, neither the first nor the second phase of the f-Met-Leu-Phe (fMLP)-induced calcium response was inhibited by any of the cAMP-active agents tested. Indeed, at low concentrations of fMLP, a combination of forskolin and rolipram caused slight enhancement of the calcium response. This result was consistent with the observations that these agents had no effect or caused slight enhancement of histamine or leukotriene released induced by fMLP. Similarly, cAMP-active agents caused no inhibition of C5a or phorbol ester (phorbol myristate acetate)-induced histamine release. These observations suggest that inhibition of the phase of the calcium response that is dependent on extracellular calcium could account for the inhibition of histamine release by these agents. However, these studies also suggested that (1) this is effect is not exerted at the level of the inositol trisphosphate (InsP3) receptor or InsP3 metabolism and (2) the mechanisms that maintain the second-phase calcium response are possibly distinct for IgE- and fMLP-mediated reactions because cAMP-active agents inhibited the second-phase response of only one stimulus.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Differing mechanisms of cAMP- versus seawater-induced oocyte maturation in marine nemertean worms II. The roles of tyrosine kinases and phosphatases.

Instead of blocking oocyte maturation as it does in most animals, cAMP causes oocytes of marine nemertean worms to initiate maturation (=germinal vesicle breakdown, "GVBD"). To characterize cAMP-induced GVBD in nemerteans, inhibitors of tyrosine kinase signaling were tested on Cerebratulus sp. oocytes that had been incubated in cAMP-elevating drugs versus seawater (SW) alone. Such tests yielded similar results for Src-like tyrosine kinase blockers, as the inhibitors prevented mitogen-activated protein kinase (MAPK) activation without stopping either GVBD or maturation-promoting factor (MPF) activation in both SW and cAMP-elevating treatments. Alternatively, genistein, a general tyrosine kinase antagonist, and piceatannol, an inhibitor of the tyrosine kinase Syk, reduced GVBD and MAPK/MPF activities in SW-, but not cAMP-induced maturation. Similarly, inhibitors of the human epidermal growth factor receptor-2 (HER-2) tyrosine kinase prevented GVBD and MAPK/MPF activations in oocytes treated with SW, but not with cAMP-elevating drugs. Antagonists of either protein tyrosine phosphatases (PTPs) or the dual-specificity phosphatase Cdc25 also reduced GVBD and MAPK/MPF activities in SW-treated oocytes without generally affecting cAMP-induced maturation. Collectively, these data suggest cAMP triggers GVBD via pathways that do not require MAPK activation or several components of tyrosine kinase signaling. In addition, such differences in tyrosine kinase cascades, coupled with the dissimilar patterns of Ser/Thr kinase signaling described in the accompanying study, indicate that nemertean oocytes are capable of utilizing multiple mechanisms to activate MPF during GVBD.

Animals↗
PubMed2006

Presynaptic effectors contributing to cAMP-induced synaptic potentiation in Drosophila.

cAMP analogs and activation of adenylyl cyclase by forskolin strongly potentiate synaptic transmission at the Drosophila neuromuscular junction. These effects are generally attributed to activation of cAMP-dependent protein kinase. Recent reports on crustacean and mammalian synapses have implicated other cAMP-dependent effectors in synaptic potentiation. Drosophila neuromuscular junctions were tested for effects of two known cAMP-dependent effectors: hyperpolarization-activated, cyclic nucleotide-regulated channels (HCNCs) and guanine nucleotide exchange protein activated by cAMP (Epac). Forskolin-induced enhancement of synaptic transmission was drastically reduced by a blocker of HCNCs, but not completely eliminated. A specific agonist for Epac modestly enhanced synaptic potentials. This agonist also stabilized their amplitudes in the presence of a blocker of HCNCs. The observations implicate HCNCs and Epac in cAMP-dependent potentiation that does not require cAMP-dependent protein kinase, indicating that additional previously unexplored factors contribute to synaptic plasticity in Drosophila. Genetic and molecular techniques available for Drosophila can be used to define the underlying molecular basis for cAMP-dependent synaptic potentiation.

Animals↗
PubMed1993

Serotonin-induced increase in cAMP in ganglia isolated from the myenteric plexus of the guinea pig small intestine: mediation by a novel 5-HT receptor.

Serotonin (5-HT) is a mediator (through 5-HT1P receptors) of slow EPSPs in myenteric ganglia of the small intestine. The effect of 5-HT can be mimicked by elevating cAMP; therefore, we tested the hypothesis that the slow EPSP-like response to 5-HT is cAMP-mediated. Guinea pig gut was enzymatically dissociated; myenteric ganglia remained intact and were collected by filtration. Neurons in the isolated ganglia retained their ability to manifest the slow EPSP-like response to 5-HT. Exposure to 5-HT raised the ganglionic level of cAMP (ED50 0.3 microM). This effect was not antagonized by the 5-HT1P antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (100.0 microM), or mimicked by the 5-HT1P agonist, 5-hydroxyindalpine (10.0 microM). Increases in cAMP were also evoked by the 5-HT1 agonist, 5-carboxyamidotryptamine (10.0 microM), the 5-HT2 agonist, (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1.0-10.0 microM), and by the 5-HT4 agonists, renzapride (1.0-10.0 microM) and 5-methoxytryptamine (1.0-10.0 microM); however, neither the 5-HT1/5-HT2 antagonists, spiperone, methysergide, and methiothepin, nor the 5-HT4 antagonist, tropisetron (ICS 205-930; 10.0 microM), were able to inhibit the rise in cAMP evoked by these compounds or by 5-HT (0.1-10.0 microM). The 5-HT-evoked elevation of cAMP was antagonized by ketanserin (10.0 microM), which also blocked the effects of 5-methoxytryptamine and DOI, but not those of renzapride. The effective concentration of DOI, however, was higher than that needed for activation of 5-HT2 receptors, and Northern analysis using a cDNA probe encoding the rat 5-HT2 receptor failed to reveal the presence of 5-HT2 mRNA in myenteric ganglia, although it hybridizes with mRNA of the right size in the guinea pig brain. Compounds that failed to change levels of cAMP or to antagonize the action of 5-HT included 8-hydroxy-di-n-propylamino tetralin, R58639, R88226, and sumatriptan. It is concluded that the receptor responsible for the 5-HT-induced rise in cAMP in ganglia isolated from the guinea pig myenteric plexus is not a known subtype of 5-HT receptor. Since the pharmacology of this novel receptor is different from that of the slow EPSP-like response to 5-HT, the receptor probably does not mediate the slow EPSP.

Acetylcholinesterase↗
PubMed1994

cAMP inhibits the insulin-stimulated mitogen-activated protein kinase pathway in rat hepatoma H4EII cells.

Effects of cAMP on insulin-stimulated mitogen-activated protein (MAP) kinase pathway were examined using rat hepatoma H4EII cells. MAP kinase was rapidly activated and reached a peak 3 min after the stimulation by insulin. Forskolin (1 microM) and 8(4-chlorophenylthio)cAMP (8-CPT-cAMP) (0.1 mM) inhibited the insulin-stimulated MAP kinase activity. Pretreatment of the cells with H-8 (50 microM), a cAMP-dependent protein kinase inhibitor, enhanced the insulin-stimulated MAP kinase activity and partially restored the inhibitory effect of cAMP. Furthermore, insulin-induced phosphorylation of MAP kinase was inhibited by 8-CPT-cAMP, and the inhibition was restored by H-8. 8-CPT-cAMP did not inhibit the autophosphorylation of insulin receptor. These data indicate that elevation of intracellular cAMP blocks the insulin-stimulated MAP kinase pathway downstream of insulin receptor.

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

Human regulatory subunit RI beta of cAMP-dependent protein kinases: expression, holoenzyme formation and microinjection into living cells.

The human regulatory subunit RI beta of cAMP-dependent protein kinases was expressed in Escherichia coli as a fusion protein with glutathione S-transferase. Purification was performed by affinity chromatography on glutathione-agarose beads after cleavage with thrombin. The human recombinant RI beta protein migrated at 55 kDa on SDS-PAGE and displayed immunoreactivity with an anti-human RI beta antiserum. Furthermore, the purified recombinant RI beta protein was shown to exist as a dimer that was able to form holoenzyme with the catalytic subunit C alpha. The rate of RI beta 2C alpha 2 holoenzyme formation was faster in the presence than in the absence of MgATP. The kinase activity measured before and after adding cAMP to the holoenzyme showed that the presence of cAMP resulted in holoenzyme dissociation and release of active C alpha-subunit, due to cAMP binding to RI beta. Compared to a RI alpha 2C alpha 2 holoenzyme, the RI beta 2C alpha 2 holoenzyme exhibited a more than twofold higher sensitivity to cAMP. The subcellular localization of RI beta was analyzed in quiescent REF-52 fibroblasts and Wistar rat thyroid (WRT) cells after microinjection of fluorescently labeled proteins into the cytoplasm. A cytoplasmic distribution was observed when free RI beta was injected, whereas free C alpha injected into the cytoplasm appeared in the nucleus. When holoenzymes with labeled RI beta and unlabeled C alpha, or unlabeled RI beta and labeled C alpha, were injected, unstimulated cells showed fluorescence in the cytoplasm of both cell types. REF-52 cells stimulated with 8-bromo-cAMP (8-Br-cAMP) and WRT cells treated with thyrotropin (TSH) showed fluorescence mainly in the cytoplasm when RI beta was the labeled subunit of the in vivo dissociated holoenzyme. In contrast, nuclear fluorescence was evident from the release and translocation of labeled C alpha from the holoenzyme complex after stimulation with 8-Br-cAMP or TSH.

Allosteric Regulation↗