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 long-term changes that occur in the gerbil brain following transient cerebral ischemia using histology and receptor autoradiography. Transient ischemia was induced for 3 and 10 min, and animals were allowed to survive for 8 months. A histological study showed that 3-min ischemia caused neuronal damage and mild atrophy only in the hippocampal CA1 sector, and that 10-min ischemia produced severe neuronal damage and marked shrinkage in the hippocampal CA1 and CA3 sectors. Furthermore, severe neuronal damage was seen in the striatum after 10-min ischemia. Autoradiography study revealed that 3-min ischemia caused a significant reduction in [3H] naloxone binding in the frontal cortex, striatum, dentate gyrus, and thalamus, whereas [3H]SCH 23390 and [3H] forskolin binding was not significantly altered in all regions. In contrast, 10-min ischemia produced marked alteration in these binding sites in the striatum, hippocampus, thalamus, and substantia nigra. The alteration was especially notable in the hippocampal region and substantia nigra. These results indicate that hippocampal damage after transient ischemia, compared with that in other regions, is not static, but particularly progressive. Furthermore, they demonstrate a reduction in adenylate cyclase system in the striatum and substantia nigra after transient ischemia. Moreover, our results suggest that long-term survival after ischemia may induce synaptic modification of neurotransmitter and adenylate cyclase system in the hippocampus.
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PMID:Long-term observations in gerbil brain following transient cerebral ischemia: autoradiographic and histological study. 827 28

Neurotransmitter receptor-coupled mechanisms have been recently recognized as important determinants of cell damage after central nervous system (CNS) trauma and ischemia. Many of these receptors exert their intracellular effects via second messenger systems. This study used in vitro autoradiographic radioligand binding to measure beta-adrenergic and muscarinic cholinergic receptors and adenylate cyclase and protein kinase C (PKC) binding sites two h after acute subdural hematoma in rats. Both beta-adrenergic and cholinergic receptor binding sites were unchanged in comparison to controls, while adenylate cyclase binding significantly decreased in the ischemic cortex under the hematoma. These changes may constitute a major limiting factor on receptor-linked therapeutic strategies in trauma and ischemia. Protein kinase C activation significantly increased in the ischemic area under the hematoma in these studies. This appears to be a response to calcium flux, which may be in part glutamate mediated.
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PMID:Early changes in second messenger but not receptor binding sites after acute subdural hematoma: an in vitro autoradiographic study. 839 84

The potential usefulness of adenosine receptor stimulation in the therapy for ischemic brain disease is dependent upon retention of adenosine receptors and their transduction mechanisms after ischemia. The receptors most clearly associated with adenosine-dependent cerebral inhibition are the A1-type (A1-AR), which work via a Gi protein to inhibit adenylate cyclase. In brain membranes from rats recovering at various times after 15 min of complete cardiac arrest-induced ischemia, the levels of A1-AR decreased temporarily to 60% of the control values. However, agonist affinities for A1-AR, as well as guanine nucleotide-sensitive high-affinity binding, remain unchanged. The significant decrease of agonist affinities to A1-AR produced by calcium depletion in control membranes was markedly attenuated after ischemia. Moreover, the A1-AR agonist-induced inhibition of cAMP production parallels the decrease in these receptor numbers. It was blocked in the postischemic membranes but reverts to control levels upon extending the recovery period to one week after the insult. It is concluded that in addition to the lowering of the number of A1-AR binding sites, the coupling of A1 receptor activation to adenylate cyclase response is inhibited after ischemia, but not at the level of receptor-Gi protein interaction.
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PMID:Coupling of adenosine receptors to adenylate cyclase in postischemic rat brain. 839 99

Myocardial dysfunction following prolonged ischemia and reperfusion is at least partially dependent upon adhesion of neutrophils to myocardial and endothelial cells. Neutrophils are thought to contribute to reperfusion injury by two mechanisms: impairment of the microvasculature by physical obstruction, and secretion of products that damage microvasculature and myocardium. Cytokines have been shown to play several roles in neutrophil aggregation. Interleukin-6 (IL-6), along with IL-1 and tumor necrosis factor-alpha (TNF-alpha), induces the expression of intracellular adhesion molecule-1 (ICAM-1) in myocytes and endothelial cells, respectively. These cytokines also inhibit contractility and nitric oxide release (a vasodilator), and IL-1 and TNF-alpha have been found to reduce adrenergic stimulation of myocardial contractility by reducing intracellular cyclic AMP levels and uncoupling adenylate cyclase from beta receptors. The transforming growth factors, TGF-alpha and TGF-beta, also have a role in reperfusion injury. TGF-alpha reduces endothelial cell release of nitric oxide, while TGF-beta appears to protect against reperfusion injury by reducing plasma TGF-alpha levels, blocking neutrophil adherence, and promoting nitric oxide release. Although cytokines are likely to have important roles in reperfusion injury, their involvement in myocardial stunning is unclear.
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PMID:Cytokines and reperfusion injury. 846 22

During myocardial ischemia, a local release of noradrenaline coincides with an increased density of beta-adrenergic receptors. The functional activity of these receptors, however, is mainly determined by their state of phosphorylation. The beta-adrenergic receptor kinase (beta ARK) specifically phosphorylates and thereby inactivates beta-adrenergic receptors after stimulation by receptor agonists, facilitating the binding of the inhibitor protein beta-arrestin to the receptors. beta ARK activation involves a translocation of the enzyme to the membrane. In the present study, we investigated the density and the functional activity of beta-adrenergic receptors, the enzymatic activity of beta ARK in membranes and cytosol, the mRNA levels of beta ARK-1, and the expression of beta-arrestin during stop-flow and low-flow ischemia in the isolated perfused rat heart. After 60 minutes of stop-flow ischemia, beta-adrenergic receptor density was upregulated, but beta-agonist-mediated adenylate cyclase activity was blunted. Simultaneously, beta ARK activity in the particulate fraction was significantly induced. The increase in beta ARK activity was reversible after inhibition of ischemia-evoked noradrenaline release by desipramine. Also, exposure to externally given noradrenaline increased beta ARK activity in the particulate fraction. Cytosolic beta ARK activity remained largely unchanged during stop-flow or low-flow ischemia. The steady state concentration of beta ARK-1 mRNA increased after 20 minutes of stop-flow ischemia and then returned to baseline values after another 20 minutes. Cardiac ischemia did not alter beta-arrestin levels. During myocardial ischemia, an increase in the number of beta-adrenergic receptors is paralleled by increased membrane activity of the receptor kinase beta ARK. This increased membrane activity may contribute to enhanced receptor phosphorylation and inactivation.
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PMID:Activation of beta-adrenergic receptor kinase during myocardial ischemia. 878 79

Guanine nucleotide-binding regulatory proteins (G proteins) play a major role in the regulation of a number of physiological processes, such as stimulation or Inhibition of adenylate cyclase activity or gaiting of ionic channels. Myocardial ischemia could induce the changes in receptor-G protein signal transduction system in the heart. Therefore, this article will focus on the role and alterations of G proteins (especially, Gs and Gi) in myocardial ischemia. The Gi protein rapidly loses functional activity during very early myocardial ischemia. In contrast to Gi protein, the function of Gs protein during this phase has not been evaluated. Moreover, the changes in Gs protein after 30 min of ischemia are contradictory. However, the sensitization of the adenylate cyclase activity in the very early phase of acute ischemia is gradually replaced by a decrease in adenylate cyclase activity with prolonged ischemia. The decrease in the function and amount of Gs protein may be one of the factors that induce these changes. The function of Gs protein was also decreased in the canine hearts with ischemia and reperfusion. In contrast to ischemia and reperfusion, there are no significant alterations in G proteins and modulation of adenylate cyclase in the stunned myocardium. It has become increasingly evident that Gi protein may play an important role in the cardioprotective effects of preconditioning. When beta-adrenoreceptor densities are reduced in chronic myocardial ischemia, decreased in the amount and function of Gi protein and increased amount of Gs protein may play the role in preservation of the adenylate cyclase activity. These alterations in G proteins may play the important role in the myocardial function during myocardial ischemia.
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PMID:The guanine nucleotide-binding regulatory proteins (G proteins) in myocardium with ischemia. 890 69

One or several brief episodes of myocardial ischemia (ischemic preconditioning; IP) rapidly induces tolerance to a later ischemic challenge. This endogenous cardioprotective effect is characterized by a slower onset of cell death. A key feature and probable proximate mechanism of IP is reduced ischemic energy demand which is evident by slower use of ATP and slower accumulation of ischemic catabolites. Several mechanisms for IP and the associated metabolic slowing have been studied: The mitochondrial ATPase is a major cause of ATP hydrolysis in ischemic myocardium but slower ATP depletion in preconditioned myocardium is not due to persistent inhibition of this ATPase. Brief episodes of ischemia in dogs induce stunning as well as IP. Stunning, however, is neither necessary nor sufficient to establish the protective effects of IP. Release of norepinephrine from adrenergic cardiac nerves causes beta adrenergic receptor-mediated stimulation of adenylate cyclase, which stimulates energy-dependent processes. However, IP in dogs that were depleted of catecholamines by pretreatment with reserpine was less effective than IP in control hearts. Thus, an antiadrenergic mechanism does not fully account for the preconditioned state. Another proposed mechanism involves earlier or more complete opening of ATP-sensitive potassium (KATP+) channels. Which of these (or other) pathways mediate the energy sparing effects of ischemic preconditioning remains unknown.
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PMID:The slowing of ischemic energy demand in preconditioned myocardium. 890 52

Adenosine participates in the physiology of central and peripheral tissues through several subtypes of G-protein-coupled receptors. Positively linked to adenylate cyclase, A2 receptors have been subdivided into A2a and A2b sites on the basis of their molecular, biochemical and pharmacological properties. They exhibit selective distribution, and are implicated in the modulation of psychomotor activity, circulation, respiration, and metabolism. Recent data support the evidence that adenosine A2 receptor properties may prove useful in future drug development, and selective manipulation of receptor-associated biologic effects might be relevant in the treatment of various disorders, including psychiatric diseases, hypoxia/ischemia, inflammation or erythrocytosis.
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PMID:Adenosine physiology and pharmacology: how about A2 receptors? 894 Jul 47

To explore alterations in messenger RNA (mRNA) for the beta-adrenoceptor (beta-AR) in ischemic myocardium, we compared the mRNA levels for beta-AR in ischemic and nonischemic myocardium by in situ hybridization using a radioisotope imaging system. We also compared these mRNA levels in ischemic and nonischemic myocardium with the number of the beta-AR by radioligand binding assay. The mRNAs for beta-AR were diffusely distributed in normal hearts. The level of mRNA detected by in situ hybridization was reduced by acute ischemia, whereas the number of beta-AR was increased. Although the number of beta-AR was increased in the myocardium with one or three hours ischemia, the total function in beta-AR-stimulatory G protein-adenylate cyclase system was not changed. There is a discrepancy between beta-AR mRNA and protein levels in the acute ischemic rat ventricular myocardium.
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PMID:Dissociation of beta-adrenoceptor numbers from mRNA levels during acute ischemia in rat myocardium. 903 30

Carpal tunnel release is the most common hand operation performed in this country. In the absence of specific systemic diseases, the etiology and persistence of pain and dysfunction even after surgical decompression is poorly understood. The focus of this investigation was to investigate the biological factors present within the patients serum that may lead to increased sensitivity to pain. Tissue was collected from patients during surgery. The tissue was homogenized and the homogenate analyzed for the presence of IL-1, IL-6, prostaglandin E series (PGE2). The levels were compared with volunteers that had no evidence of carpal tunnel syndrome or pain. The results showed similar levels of IL-1 (range 42-26 ng/ml) in tissue homogenates, and a significant increase in levels of IL-6 and malionaldehyde bis-(diethyl acetal) in CTS patients in comparison to control tissues. This increase may be associated with oxidative changes occurring as a result of ischemia and reperfusion. Tissue homogenates were also evaluated for PGE2. The CTS tissues showed a five fold elevation in PGE2 compared to control tissues. Levels of PGE2 in CTS tissues were statistically different using a two-tailed student T-test. Increased levels of PGE2 can enhance vascular permeability at the site of injury, and can play an important role in activating adenylate cyclase which increases intracellular cyclic adenosine monophosphate (cAMP). This increase in cAMP levels can inhibit functional responses to other inflammatory stimuli. Increases in PGE2 can also cause sensitization of the nerve endings so that a normal stimulus that would not necessarily cause pain will now be experienced as painful. The results of this study demonstrate that arachidonic acid metabolites PGE2 may be responsible for both the pathological changes and clinical symptomatology in carpal tunnel syndrome.
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PMID:Biochemical and histological analysis of the flexor tenosynovium in patients with carpal tunnel syndrome. 973 66


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