Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of mouse colliculi neurons to selective 5-hydroxytryptamine (5-HT)4 agonists was accompanied by a rapid desensitization of the receptor-stimulated adenylyl cyclase response. Half-maximal desensitization occurred after 2 min. Only exposure of neurons to selective 5-HT4 agonists led to a potent desensitization of the 5-HT4-mediated response. Neurons exposed to other agents, like isoproterenol, vasoactive intestinal peptide, or forskolin, that increase cAMP levels did not undergo any desensitization of 5-HT4 receptors. Activation of protein kinase A with either 8-bromo-cAMP or dibutyryl-cAMP or application of inhibitors of protein kinase A-dependent phosphorylation did not change the rate of 5-HT4-induced desensitization. No shift to lower potency of 5-HT4 agonists in the concentration-response curve was observed. These results suggest that 5-HT4 receptor agonists induced homologous but not cAMP-mediated heterologous desensitization. A good correlation was found between the affinities of nine 5-HT4 agonists and their abilities to desensitize the adenylyl cyclase response. This may indicate that homologous desensitization is a function of the mean occupancy time of the receptors by agonists. When permeabilized neurons were loaded with heparin, an inhibitor of the beta-adrenergic receptor kinase (beta ARK), 5-HT4 receptor desensitization was reduced by 30-40%. Interestingly, Zn2+, an other inhibitor of beta ARK, totally prevented 5-HT4-induced desensitization. Pretreatment of neurons with concanavalin A, reported to inhibit sequestration of beta-adrenergic receptors from the cell surface, reduced the desensitization process by 70%. These data suggest that both sequestration and phosphorylation by beta ARK, or another specific agonist-dependent receptor kinase, are involved in homologous desensitization of 5-HT4 receptors coupled to adenylyl cyclase.
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PMID:Characterization of homologous 5-hydroxytryptamine4 receptor desensitization in colliculi neurons. 133 63

By means of dual immunohistochemical labeling on the same brain section examined with a light microscope, the present study reports the presence with serotonin (5-hydroxytryptamine; 5-HT) of gamma-aminobutyric acid (GABA), substance P (SP), thyrotropin-releasing hormone (TRH), leucin-enkephalin (LEU-enk), or methionine-enkephalin (MET-enk), within the same neuron in the nuclei raphe magnus, raphe obscurus, and raphe pallidus of the rat. On the one hand, peptides or GABA are detected with specific rabbit antibodies by indirect peroxidase labeling using peroxidase-conjugated Fab fragments, and on the other, 5-HT is detected with a rabbit antibody against the BSA-serotonin conjugate by radio-immunocytochemistry using [125I]-labeled protein A. The possible coexistence of TRH and SP in these neurons is also investigated by using peroxidase labeling and radio-immunocytochemical detection, respectively. In the whole caudal raphe nuclei the proportion of each coexisting peptide with 5-HT appears in decreasing order as: TRH greater than SP greater than MET-enk # LEU-enk greater than GABA. In all instances the level of coexistence differs considerably in B1-B2 vs. B3 cell groups. No SP/TRH dually labeled cells have ever been found in any of the serotonergic nuclei of the caudal raphe. Given the evidence that these raphe nuclei project possibly to the spinal cord, these data constitute an anatomical substrate for the several distinct physiological functions presumably subserved by 5-HT in the cord, namely the modulation of nociception, motor, and autonomic functions.
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PMID:Immunohistochemical evidence for the coexistence of substance P, thyrotropin-releasing hormone, GABA, methionine-enkephalin, and leucin-enkephalin in the serotonergic neurons of the caudal raphe nuclei: a dual labeling in the rat. 172 85

Ketanserin, a recently developed 5-HT2 receptor antagonist, competitively and selectively blocks the vasoconstrictor activity of 5-hydroxytryptamine (serotonin). We explored a possible contribution of serotonin to augmented vascular tone in patients with severe heart failure, using intravenous and oral formulations of ketanserin. When administered intravenously (10 mg bolus, 4 mg/hr infusion for +/- 40 min) to 10 patients with congestive heart failure (NYHA III or IV) secondary to congestive cardiomyopathy (n = 8) or ischemic heart disease (n = 2), the drug produced a significant increase in cardiac output (rest 24%, p less than 0.001; exercise 19%, p less than 0.01) which was accompanied by a fall in systemic arterial pressure (rest 7%, p less than 0.001; exercise 10%, p less than 0.05) and pulmonary wedge (rest 17%, p less than 0.05; exercise 23%, p less than 0.001) pressure. Calculated systemic vascular resistance (SVR, rest 27%, p less than 0.001; exercise 23%, p less than 0.05) decreased significantly. No significant hemodynamic changes were observed when 40 mg of ketanserin was administered orally to the same group of patients. Plasma catecholamines (norepinephrine, NEP:epinephrine, EP:dopamine) were measured before and after ketanserin at rest and during exercise. Baseline NEP levels were markedly elevated at rest and during exercise in all patients (rest: 878 +/- 381 ng/mL, exercise: 1453 +/- 697 ng/mL). Baseline EP levels were within normal limits. Ketanserin did not produce any change in catecholamine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic and neurohumoral effects of ketanserin, a 5-HT2 receptor antagonist in patients with congestive heart failure. 356 10

We investigated the efficacy in reducing myocardial preservation and reperfusion (P/R) injury of direct hydroxyl radical scavenging by nicaraven as compared with scavenging of both superoxide radicals and hydrogen peroxides by superoxide dismutase (SOD) and catalase (CAT), respectively. Isolated rat hearts were mounted on a Langendorff (L) apparatus to estimate the baseline aortic flow (AF), coronary flow (CF), cardiac output (CO), systolic pressure (SP), aortic mean pressure (MP), rate pressure product, and LV dp/dt. They were divided into 3 groups: group 1, 12 hr storage in HTK solution; group 2, 12 hr storage in HTK solution containing 2.5x10(5) U/L SOD and 2x10(5) U/L mg/L CAT; and Group 3, 12 hr storage in HTK solution containing 10(-3) M nicaraven. SOD, CAT, and nicaraven were administered intraperitoneally before harvesting. Hearts were stored in each preservation solution at 4, and then reperfused. Postpreservative function and concentrations of leaked enzymes were measured. The hearts were switched back to the L-mode and paced at 330 beats/min. CF following perfusion with Krebs-Henseleit bicarbonate buffer (KHB) solution containing 10(-6) M 5-hydroxytryptamine (5-HT) or 10(-5) M nitroglycerin (NTG) then evaluated. The myocardial water content also was measured. The recovery of CF, CO, SP, MP, and LV dp/dt was significantly greater in group 3 than in group 1. The recovery of CF was superior to that in group 2 (P<0.05). There were no significant differences in the recovery of cardiac function between groups 1 and 2. 5-HT caused a decrease in CF in each group, however, CF in group 3 was higher than that in group 1 (P<0.05). NTG caused no significant differences among the groups. There were no significant differences in leaked enzymes and myocardial water content among the three groups. These results suggest that nicaraven protects against myocardial P/R injury through its hydroxyl radical scavenging activity, and that therapy with oxygen-free radical scavengers should be directed toward inactivation of hydroxyl radicals rather than superoxide radicals and/or hydrogen peroxides.
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PMID:The role of a hydroxyl radical scavenger (nicaraven) in recovery of cardiac function following preservation and reperfusion. 890 Mar 8

Cholecystokinin (CCK) plays an important role in both the alimentary tract and the central nervous system (CNS). At present it seems to be the most abundant neuropeptide in the CNS. This paper reviews the CCK neuronal system and its interactions with gamma-aminobutyric acid (GABA) and serotonin (5-hydroxytryptamine; 5-HT). In addition, its putative role in anxiety will be discussed on the basis of animal data and studies in healthy volunteers and panic disorder patients. According to these investigations, the CCK4 challenge test fulfills most criteria for an ideal panicogenic agent and evidence has been found that CCKB receptor antagonists might possess anxiolytic properties in man.
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PMID:Cholecystokinin in anxiety. 898 9

This study investigated the pathways to many monoamines and their metabolites in the central nervous system of the frog Rana nigromaculata and the toad Bufo bufo japonicus during embryonic development and metamorphosis. Metabolites were analyzed by three-dimensional HPLC. The two species provided evidence of similar pathways, with slightly different timetables for the development of their monoamine systems. During embryonic development, the main metabolic pathways in entire embryos were tyrosine (TYR)-->[3,4-dihydroxyphenylalanine in Bufo]-->3-hydroxytyramine-->norepinephrine or epinine (EPIN)-->epinephrine, TYR-->tyramine--> (octopamine in Rana) and TYR-->3-O-methyldopa for catecholamines, and tryptophan-->kynurenine and 5-hydroxytryptamine (5-HT)-->[5-hydroxyindoleacetic acid and N-methyl-5-hydroxytryptamine (N-MET) in Bufo]. The monoamine system in the brain was similar during metamorphosis to that during embryogenesis with a few exceptions. The most striking change was the development of the bufotenine (5-hydroxy-N, N-dimethyltryptamine) pathway from 5-HT via N-MET. EPIN and norepinephrine in Rana and octopamine in both species disappeared during metamorphosis. These results are discussed in relation to the roles of the various pathways in development.
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PMID:The metabolism of biogenic monoamines during embryogenesis and metamorphosis in two anuran species. 920 70

In this paper, we present evidence that activation of 5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1/cdk4 and cyclin E/cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels. The induction of cyclin D1 expression, but not that of cyclin E, is under mitogen-activated protein kinase (MAPK) control, indicating an independent regulation of these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by using the specific platelet-derived growth factor receptor (PDGFR) inhibitor AG 1296 or by overexpressing a kinase-mutant PDGFR, we show that PDGFR kinase activity is essential for 5-HT2B-triggered MAPK/cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor activation also increases activity of the Src family kinase, c-Src, Fyn, and c-Yes. Strikingly, c-Src, but not Fyn or c-Yes, is the crucial molecule between the G(q) protein-coupled 5-HT2B receptor and the cell-cycle regulators. Inhibition of c-Src activity by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) or depletion of c-Src is sufficient to abolish the 5-HT-induced (i) PDGFR tyrosine kinase phosphorylation and MAPK activation, (ii) cyclin D1 and cyclin E expression levels, and (iii) thymidine incorporation. This paper elucidates a model of 5-HT2B receptor mitogenesis in which c-Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase PDGFR to induce cyclin D1 expression via the MAPK/ERK pathway.
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PMID:5-hydroxytryptamine 2B receptor regulates cell-cycle progression: cross-talk with tyrosine kinase pathways. 1068 5

Medications that selectively increase 5-hydroxytryptamine are currently the most commonly prescribed antidepressants. However, it is not known which receptors for 5-hydroxytryptamine, nor which post-receptor cellular signals, mediate the antidepressant actions of 5-hydroxytryptamine. The hippocampus is highly innervated by serotonergic neurons and appears to be an ideal region of the brain for studying the antidepressant role of 5-hydroxytryptamine. Treatment with antidepressants has been shown to cause increased expression of proteins in the hippocampus that appear to be protective against stress-induced atrophy. This suggests a role for pathways, such as mitogen-activated protein kinase, that regulate protein synthesis. In the present study we found that 5-HT(7) receptors, expressed by cultured rat hippocampal neurons, couple to stimulation of the mitogen-activated protein kinase extracellular signal-regulated kinases ERK1 and ERK2. The 5-HT(1/7) receptor-selective agonist 5-carboxamidotryptamine maleate (5-CT) as well as the 5-HT(1A/7) receptor-selective agonists 8-hydroxy-N,N-dipropyl-aminotetralin (8-OH-DPAT) and N,N-dipropyl-5-carboxamidotryptamine maleate (dipropyl-5-CT) were found to activate extracellular signal-regulated kinase with equal efficacy to 5-HT. However, the EC(50) for 8-OH-DPAT was approximately 200-fold greater than that of 5-HT, a difference in potency consistent with the pharmacology of 5-HT(7), but not 5-HT(1A), receptors. Additionally, pretreatment with pertussis toxin, which would be expected to block the actions of 5-HT(1,) but not 5-HT(7,) receptors caused no inhibition. 4-Iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]N-2-pyridinyl-benzamide hydrochloride (p-MPPI) and N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarb oxamide maleate (WAY-100635), antagonists selective for 5-HT(1A) receptors, similarly caused no inhibition of the activity of 5-HT.In summary, these studies are the first to demonstrate that 5-hydroxytryptamine activates the mitogen-activated protein kinase ERK in primary neuronal cultures. That 5-HT(7) receptors couple to activation of extracellular signal-regulated kinase in hippocampal neurons suggests a possible role for 5-HT(7) receptors in mediating some of the actions of antidepressants that increase 5-hydroxytryptamine.
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PMID:5-HT(7) receptors activate the mitogen activated protein kinase extracellular signal related kinase in cultured rat hippocampal neurons. 1116 22

Biogenic amine transporters, namely the dopamine (DA), norepinephrine (NE) and 5-hydroxytryptamine (serotonin, 5-HT) transporters (DAT, NET and 5-HTT, respectively) appear to be the key elements in regulating biogenic amine neurotransmission. These proteins therefore represent a primary target for therapeutic intervention in the treatment of numerous psychiatric disorders, such as depression, anxiety and perhaps even schizophrenia as well as drug abuse. The cloning of DAT, NET and 5-HTT and development of selective radioligands for them over the last decade has dramatically increased our understanding of their location, structure and function. These breakthroughs have also enabled remarkable progress in determining how biogenic amine transporters are regulated under not only normal conditions but also when confronted with acute or chronic exposure to a variety of stimuli including psychotherapeutic drugs. Because of the important therapeutic consequences of a better understanding of these transporters, the present review discusses recent advances in defining their mechanism of action, location and regulation and the implications of the newer data for neuropsychopharmacology.
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PMID:New views of biogenic amine transporter function: implications for neuropsychopharmacology. 1128 47

The effects of nicotinic agonists and antagonists on whole-cell currents and 5-hydroxytryptamine (5-HT) release were studied in order to characterize nicotinic ACh receptors on the 5-HT-containing chemoreceptor cells of the chicken aorta. ACh, nicotine and dimethylphenylpiperazinium (DMPP) evoked concentration-dependent inward currents accompanied by increases in current noise at a holding potential of -70 mV. The peak amplitude of the current response to DMPP was 50% larger than that to either nicotine or ACH: Hexamethonium, alpha - bungarotoxin (alpha - BTX) and methyllycaconitine decreased nicotine-induced inward currents in a concentration-dependent manner. Although hexamethonium (0.1 mM) abolished the current response to nicotine (30 microM), a high concentration (1 microM) of alpha - BTX decreased it only by about 30% of the control response. Methyllycaconitine (0.1 microM) decreased the current response to nicotine to the same extent as did alpha - BTX whilst a high concentration (10 microM) abolished the response. ACh, nicotine and DMPP caused concentration-dependent increases in 5-HT output from the thoracic aorta which effect was blocked by hexamethonium (0.1 mM). Pre-treatment with alpha - BTX (1 microM) for 30 min reduced the output of 5-HT induced by ACh to 70% of the control response. It is suggested that neuronal nicotinic ACh receptors, sensitive and insensitive to alpha - BTX, are present on the chemoreceptor cells of the chicken aorta, the activation of which causes the release of 5-HT.
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PMID:Heterogeneity of neuronal nicotinic acetylcholine receptors in 5-HT-containing chemoreceptor cells of the chicken aorta. 1130 66


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