Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment of human peripheral blood monocytes with serotonin at concentrations 10(-3) and 10(-5) M over 20 minutes decreases a zymosan-induced luminol-dependent chemiluminescence of cells, whereas a 5 minutes treatment with serotonin at the concentration of 10(-5) M increases the chemoluminescence. The correlated change in monocyte capacity of secreting hydrogen peroxide has been registered. Serotonin activates, to a little extent, the monocyte capacity of phagocytizing the opsonised sheep erythrocyte. The maximum increase (2-3 times) of intracellular cAMP content and the decrease in cytosol cAMP-binding capacity are registered after a 5 minutes incubation. The lowering of the share of irreversibly bound in vitro cAMP under the influence of serotonin may suggest a preferable binding of cyclic nucleotide in vivo by regulatory subunits of cAMP-dependent protein kinase I.
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PMID:[The effect of serotonin on the functional activity of monocytes]. 165 Sep 68

A model that summarizes some of the neural and molecular mechanisms contributing to short- and long-term sensitization is shown in Figure 14. Sensitizing stimuli lead to the release of a modulatory transmitter such as 5-HT. Both serotonin and sensitizing stimuli lead to an increase in the synthesis of cAMP and the modulation of a number of K+ currents through protein phosphorylation. Closure of these K+ channels leads to membrane depolarization and the enhancement of excitability. An additional consequence of the modulation of the K+ currents is a reduction of current during the repolarization of the action potential, which leads to an increase in its duration. As a result, Ca2+ flows into the cell for a correspondingly longer period of time, and additional transmitter is released from the cell. Modulation of the pool of transmitter available for release (mobilization) also appears to occur as a result of sensitizing stimuli. Recent evidence indicates that the mobilization process can be activated by both cAMP-dependent protein kinase and protein kinase C. Thus, release of transmitter is enhanced not only because of the greater influx of Ca2+ but also because more transmitter is made available for release by mobilization. The enhanced release of transmitter leads to enhanced activation of motor neurons and an enhanced behavioral response. Just as the regulation of membrane currents is used as a read out of the memory for short-term sensitization, it also is used as a read out of the memory for long-term sensitization. But long-term sensitization differs from short-term sensitization in that morphological changes are associated with it, and long-term sensitization requires new protein synthesis. The mechanisms that induce and maintain the long-term changes are not yet fully understood (see the dashed lines in Fig. 14) although they are likely to be due to direct interactions with the translation apparatus and perhaps also to events occurring in the cell nucleus. Nevertheless, it appears that the same intracellular messenger, cAMP, that contributes to the expression of the short-term changes, also triggers cellular processes that lead to the long-term changes. One possible mechanism for the action of cAMP is through its regulation of the synthesis of membrane modulatory proteins or key effector proteins (for example, membrane channels). It is also possible that long-term changes in membrane currents could be due in part to enhanced activity of the cAMP-dependent protein kinase so that there is a persistent phosphorylation of target proteins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neural and molecular bases of nonassociative and associative learning in Aplysia. 167 7

Serotonin (5-HT) shifts the phase of the circadian oscillator of the eye of Aplysia californica in a phase dependent manner. This indicates that 5-HT acts, either directly or through some intermediaries, on a component of the oscillator. Since our goal is to identify the components of the oscillator, we are following the pathway through which 5-HT has its effect on the rhythm. The effect of 5-HT on the rhythm has been shown to be mediated by an increase in intracellular cyclic adenosine-3',5'-monophosphate (cAMP). The most likely action of cAMP is to activate cAMP-dependent protein kinase. Therefore, we used two-dimensional polyacrylamide gel electrophoresis to investigate changes in 32P labelled phosphoproteins which occur with 5-HT and other treatments. Fourteen proteins showed increased incorporation of 32P when eyes were exposed to treatments of 5-HT from CT 06 to 12. Two proteins showed decreased incorporation. 8-bt-cAMP mimicked all but one of the increases and both decreases in incorporation produced by 5-HT. 8-bt-cAMP increased incorporation into three additional proteins and decreased incorporation into three others that were not affected by 5-HT. Incorporation into one protein was increased by 5-HT but decreased by 8-bt-cAMP. By comparison, light, which has little or no effect on the rhythm at this phase, only affected one protein. The protein increased by light was also increased by 5-HT. Tetradecanoic phorbol acetate (TPA), administered during CT 06-12, also had little effect on the rhythm at this phase. TPA increased incorporation into twenty proteins and decreased incorporation into three.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in protein phosphorylation in the eye of Aplysia associated with circadian rhythm regulation by serotonin. 215 3

Important findings on the molecular and regulatory properties of neurotransmitter receptors, GTP-proteins, ion channels and protein kinases were briefly reviewed. On the basis of recent advances in the theme mentioned above, we investigated the transmembrane signalling mechanism of serotonin (5-HT)-evoked inward current responses under the voltage clamp condition (holding at -60mV) in Xenopus oocytes injected with rat brain poly (A)+ mRNA, suggesting that 5-HT evokes a Cl- current via such a mechanism as follows: 1) activation of 5-HT1c subtype of receptors, 2) activation of pertussis toxin-sensitive Gi/G0, 3) phospholipase C activation, 4) inositol 1,4,5-trisphosphate (IP3) formation, 5) an increase of [Ca2+]i liberated by IP3, and 6) gating of Cl channels stimulated perhaps by Ca2+-calmodulin. On the other hand, protein kinase C (C-kinase) activation by diacylglycerol and Ca2+ seems to cause a feedback inhibition to the 5-HT responses by phosphorylation of certain proteins. Voltage-operated Ca channels of the N-type reconstituted in oocytes injected with brain mRNA seem to be modulated by C-kinase as well as by cAMP-dependent protein kinase. Significances of oocytes using as a model system to analyze the molecular mechanism of neuronal signalling in the brain were stressed and reviewed.
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PMID:[Recent advances in molecular pharmacology of cellular signalling mechanism]. 247 36

In response to the facilitating neurotransmitter serotonin (5-HT), the cAMP-dependent protein kinase (PKA) acquires a special mnemonic characteristic in Aplysia sensory neurons. PKA becomes persistently activated at basal cAMP concentrations owing to a decreased regulatory (R) to catalytic (C) subunit ratio. We previously implicated ubiquitin-mediated proteolysis in this selective loss of R. Here we show that ubiquitin (Ub), Ub-conjugates and proteasomes are present in cell bodies, axon, neuropil and nerve terminals of Aplysia neurons. Because R subunits are not decreased in muscle exposed to 5-HT, comparison of the two tissues provides a tractable approach to determine how the Ub pathway is regulated. We compared the structure of M1, the muscle-specific R isoform, to that of N4, a major neuronal R isoform, to rule out the possibility that the differences in their stability result from differences in structure. We present evidence that N4 and M1 are encoded by identical transcripts; they also behave similarly as protein substrates for the Ub pathway in extracts of the two tissues. Nervous tissue contains 20-times more free Ub, but we present evidence that the susceptibility of R subunits to degradation in neurons relative to muscle results from the greater capacity of neurons to degrade ubiquitinated proteins through the proteasome. Thus, factors that regulate the activity of proteasomes could underlie the enhanced degradation of R subunits in long-term sensitization.
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PMID:Persistent activation of cAMP-dependent protein kinase by regulated proteolysis suggests a neuron-specific function of the ubiquitin system in Aplysia. 747 10

The enhancement of excitability in type B photoreceptors is an important neural mechanism underlying classically conditioned suppression of phototaxis in the marine mollusk Hermissenda crassicornis. However, the possibility that type B photoreceptors also exhibit synaptic plasticity has not previously been explored. We now report that connections of type B photoreceptors onto type A photoreceptors exhibit synaptic facilitation, and that this facilitation involves the same first messenger (5-HT) and second messenger (protein kinase C) previously implicated in the learning-produced excitability changes. In brief, we found that application of 5-HT dramatically facilitates synaptic potentials evoked by type B cells in type A cell cells, and that this facilitation is blocked by preincubation with staurosporine, a protein kinase inhibitor. Furthermore, activation of protein kinase C also induces synaptic facilitation, whereas activation of the cAMP-dependent protein kinase has no effect. Changes in synaptic strength produced by these manipulations are paralleled by changes in type B cell input resistance (a simple index of cellular excitability), whereas type A cell input resistance is unaffected. These findings indicate a previously unrecognized form of neuronal plasticity in Hermissenda that may contribute importantly to the learned changes in behavior, and thereby highlight general principles of learning-related neuronal plasticity shared by different preparations and species.
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PMID:Synaptic facilitation at connections of Hermissenda type B photoreceptors. 812 58

The effects of increases in cellular adenosine 3'5'-cyclic monophosphate (cAMP) on 5-hydroxytryptamine-(5-HT-) induced generation of inositol phosphates (IPs) and increases in intracellular Ca2+ ([Ca2+]i) were investigated using canine cultured tracheal smooth muscle cells (TSMCs). Cholera toxin and forskolin induced concentration- and time-dependent cAMP formation with half-maximal effects (-logEC50) produced at concentrations of 7.0 +/- 0.5 and 4.9 +/- 0.4 respectively. Pretreatment of TSMCs with either forskolin or dibutyryl cAMP inhibited 5-HT-stimulated responses. Even after treatment for 24h, these agents still inhibited the 5-HT-induced Ca2+ mobilization. The inhibitory effects of these agents produced both depression of the maximal response and a shift to the right of the concentration response curves of 5-HT. The water-soluble forskolin analogue L-858051 [7-deacetyl-7beta-(gamma-N-methylpiperazino)-butyryl forskolin] significantly inhibited the 5-HT-stimulated accumulation of IPs. In contrast, the addition of 1,9-dideoxy forskolin, an inactive forskolin analogue, had little effect on this response. Moreover, SQ-22536 [9-(tetrahydro-2-furanyl)-9-H-purin-6-amine], an inhibitor of adenylate cyclase, and both H-89 [N-(2-aminoethyl)-5-isoquinolinesulphonamide] and HA-1004[N-(2-guanidinoethyl)-5-isoquinolinesulphonamide], inhibitors of cAMP-dependent protein kinase (PKA), attenuated the ability of forskolin to inhibit the 5-HT-stimulated accumulation of IPs. These results suggest that activation of cAMP/PKA was involved in these inhibitory effects of forskolin. The AlF4--induced accumulation of IPs was inhibited by forskolin, suggesting that G protein(s) are directly activated by AlF4-- and uncoupled from phospholipase C by forskolin treatment. These results suggest that activation of cAMP/PKA might inhibit the 5-HT-stimulated phosphoinositide breakdown and consequently reduce the [Ca2+]i increase or inhibit both responses independently.
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PMID:Regulation of 5-hydroxytryptamine-induced calcium mobilization by cAMP-elevating agents in cultured canine tracheal smooth muscle cells. 876 73

Long-term facilitation of the connections between the sensory and motor neurons of the gill-withdrawal reflex in Aplysia requires five repeated pulses of serotonin (5-HT). The repeated pulses of 5-HT initiate a cascade of gene activation that leads ultimately to the growth of new synaptic connections. Several genes in this process have been identified, including the transcriptional regulators apCREB-1, apCREB-2, apC/EBP, and the cell adhesion molecule apCAM, which is thought to be involved in the formation of new synaptic connections. Here we report that the transcriptional regulators apCREB-2 and apC/EBP, as well as a peptide derived from the cytoplasmic domain of apCAM, are phosphorylated in vitro by Aplysia mitogen-activated protein kinase (apMAPK). We have cloned the cDNA encoding apMAPK and show that apMAPK activity is increased in sensory neurons treated with repeated pulses of 5-HT and by the cAMP pathway. These results suggest that apMAPK may participate with cAMP-dependent protein kinase during long-term facilitation in sensory cells by modifying some of the key elements involved in the consolidation of short- to long-lasting changes in synaptic strength.
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PMID:Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons of Aplysia. 946 8

Neurotransmitter receptors are often colocalized in a neuron with other receptors, and activation of one receptor can either amplify or antagonize the response to a colocalized receptor. The aim of this study was to investigate the cross-regulation of synaptic transmission by beta-adrenergic and serotonin 1A (5-HT1A) receptors and to elucidate their underlying mechanisms. Stimulation of presynaptic beta-adrenergic receptors with isoproterenol (Iso) in the basolateral amygdala resulted in a long-lasting increase in synaptic transmission. This effect was mimicked by forskolin, an activator for adenylyl cyclase and a cAMP analog. In addition, the effect of forskolin was blocked by catalytic and regulatory site antagonists for cAMP-dependent protein kinase (PKA), indicating a PKA-mediated mechanism. Application of 5-HT depressed the synaptic transmission and blocked Iso- and forskolin-induced potentiation. The effect of 5-HT was mimicked by the selective 5-HT1A agonist 8-hydroxy-dipropylaminotetralin and was blocked by the selective 5-HT1A antagonist 1-(2-methoxyphenyl)-4[4-(2-phthalimido)butyl]piperazine, indicating its mediation by 5-HT1A receptors. To determine the locus of interaction, Sp-cAMPS, a membrane-permeable activator of PKA, was applied, and the potentiation produced by Sp-cAMPS was completely blocked in slices pretreated with 5-HT. These results suggest that the interaction between the intracellular signaling pathways activated by 5-HT1A and beta-adrenergic receptors occurs at a step downstream from cAMP production.
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PMID:Cross-modulation of synaptic plasticity by beta-adrenergic and 5-HT1A receptors in the rat basolateral amygdala. 988 May 77

Nociceptive sensory neurons (SNs) in Aplysia provide useful models to study both memory and adaptive responses to nerve injury. Induction of long-term memory in many species, including Aplysia, is thought to depend on activation of cAMP-dependent protein kinase (PKA). Because Aplysia SNs display similar alterations in models of memory and after nerve injury, a plausible hypothesis is that axotomy triggers memory-like modifications by activating PKA in damaged axons. The present study disproves this hypothesis. SN axotomy was produced by (1) dissociation of somata from the ganglion [which is shown to induce long-term hyperexcitability (LTH)], (2) transection of neurites of dissociated SNs growing in vitro, or (3) peripheral nerve crush. Application of the competitive PKA inhibitor Rp-8-CPT-cAMPS at the time of axotomy failed to alter the induction of LTH by each form of axotomy, although the inhibitor antagonized hyperexcitability produced by 5-HT application. Strong activation of PKA in the nerve by coapplication of a membrane-permeant analog of cAMP and a phosphodiesterase inhibitor was not sufficient to induce LTH of either the SN somata or axons. Furthermore, nerve crush failed to activate axonal PKA or stimulate its retrograde transport. Therefore, PKA activation plays little if any role in the induction of LTH by axotomy. However, the expression of LTH was reduced by intracellular injection of the highly specific PKA inhibitor PKI several days after nerve crush. This suggests that long-lasting activation of PKA in or near the soma contributes to the maintenance of long-term modifications produced by nerve injury.
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PMID:Activation of protein kinase A contributes to the expression but not the induction of long-term hyperexcitability caused by axotomy of Aplysia sensory neurons. 995 2


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