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 peptidergic bag cell neurons of the opisthobranch mollusc Aplysia control egg laying and its correlated behavior by release of the neuroactive peptide, egg-laying hormone, during the extended electrical discharge termed afterdischarge. This paper examines the evidence for the involvement of cyclic AMP (cAMP) and protein phosphorylation in the mediation of this electrical afterdischarge. It is concluded that an important component in the mechanism of afterdischarge is the suppression of a potassium channel, mediated by cAMP-dependent protein kinase-induced protein phosphorylation. The exact identity of the potassium channel remains to be worked out.
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PMID:Intracellular modulation of membrane channels by cyclic AMP-mediated protein phosphorylation in peptidergic neurons of Aplysia. 629

Protein substrates for an endogenous CA++/calmodulin-dependent protein kinase were characterized in the Aplysia nervous system. Ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid-washed membrane fractions from Aplysia ganglia contain an endogenous Ca++/calmodulin-dependent protein kinase which phosphorylates a number of membrane proteins. Such washed membrane preparations exhibit little or no adenosine 3':5'-cyclic phosphate (cAMP)-dependent protein kinase activity but do contain substrates for exogenously added catalytic subunit of cAMP-dependent protein kinase. Low concentrations of catalytic subunit rapidly stimulate the phosphorylation of a protein of Mr 70,000 and of a 52,000-dalton doublet, indicating that these proteins are major substrates for this enzyme. Phosphopeptide patterns obtained after limited proteolysis suggest that the 70,000-dalton protein and the 52,000-dalton doublet are similar in structure and that their phosphorylation is stimulated both by Ca++/calmodulin and by catalytic subunit. The 52,000-dalton doublet consists of two closely spaced bands: the phosphorylation of the upper band is stimulated by catalytic subunit, whereas the phosphorylation of the lower band is stimulated by the endogenous Ca++/calmodulin-dependent protein kinase. The results suggest that in Aplysia membranes a number of proteins can be phosphorylated by both Ca++/calmodulin-dependent protein kinase and catalytic subunit of cAMP-dependent protein kinase. This convergence of biochemical effects of Ca++ and cAMP may play a role in some of their physiological actions in molluscan neurons.
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PMID:Ca++/calmodulin-regulated protein phosphorylation in the Aplysia nervous system. 629 78

Previous work has shown that serotonin induces an increase in membrane K+ conductance in Aplysia neuron R15 and that this response is mediated by cAMP. The present study examines the role of protein phosphorylation in the response to serotonin. A specific inhibitor of cAMP-dependent protein kinase was injected intracellularly into neuron R15. The injection blocked the serotonin-induced increase in K+ conductance completely for at least 4 hours. The blockage was selective because the cell's response to dopamine was not inhibited. Furthermore, the blockage was specifically produced by protein kinase inhibitor because injection of other proteins (alpha-bungarotoxin and bovine serum albumin) did not affect the serotonin response. The serotonin response recovered fully 5-13 hours after the injection, presumably as a result of intracellular proteolysis of the protein kinase inhibitor. The results indicate that protein phosphorylation is a necessary step in the process that leads to activation of K+ channels by serotonin in neuron R15.
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PMID:Intracellular injection of protein kinase inhibitor blocks the serotonin-induced increase in K+ conductance in Aplysia neuron R15. 695 30

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

Application of small cardioactive peptide (SCP) or stimulation of motorneuron B15 increases the level of activated cAMP-dependent protein kinase (cAPK) in the ARC muscle. SCP application also appears to induce a translocation of cAPK between different subcellular compartments of the ARC muscle and this translocation is also induced by cAMP addition to muscle homogenates. These results suggest that the actions of SCP in the Aplysia ARC neuromuscular system are mediated via the cAPK signal transduction pathway.
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PMID:SCP application or B15 stimulation activates cAPK in the ARC muscle of Aplysia. 782 Jun 39

Myomodulin A (MMA) application or stimulation of neuron B16, which releases MMA, increases cAMP levels in the accessory radula closer (ARC) muscle of Aplysia. MMA application also increases cAMP-dependent protein kinase (cAPK) activity in one subcellular compartment of the muscle. These results suggest that at least part of MMA's effects in this system are mediated via the cAPK signal transduction pathway. Since the effects of the small cardioactive peptides (SCPs) on ARC muscle contraction are similar to those of MMA, our results suggest that the convergent physiological effects of MMA and SCPB in this system may be due, in part, to the two peptide neuromodulators utilizing the same signal transduction pathway.
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PMID:Myomodulin application increases cAMP and activates cAMP-dependent protein kinase in the accessory radula closer muscle of Aplysia. 784 14

Two type II regulatory (R) subunits of cAMP-dependent protein kinase (PKA) of 50 and 47 kDa have been identified in Aplysia neurons by several criteria which include phosphorylation by the catalytic subunit of PKA and nanomolar affinity for a peptide fragment of the human thyroid protein Ht 31, properties that in mammals distinguish type II from type I R subunits. The neuronal type II R subunits are differentially localized within cells. For example, the 50-kDa polypeptide is enriched in taxol-stabilized microtubules. In addition, at least seven high molecular mass neuronal RII-binding proteins ranging in mass from 110 to 420 kDa have been demonstrated by a blot overlay technique, which uses 32P-labeled bovine RII alpha as a probe. The RII-binding proteins also exhibit discrete patterns of subcellular localization. For example, the 420 kDa species is enriched in taxol-stabilized microtubules and therefore may serve to anchor the 50-kDa RII subunit. The localization of PKA through the association of RII subunits with the binding proteins may anchor the multifunctional kinase close to key substrates and thereby contribute to the spatial organization required to mediate the orderly phosphorylation events that underly neuronal modulation.
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PMID:Type II regulatory subunits of cAMP-dependent protein kinase and their binding proteins in the nervous system of Aplysia californica. 790 81

Acting through a cAMP-cAMP-dependent protein kinase (cAPK) cascade, members of two neuropeptide families, the small cardioactive peptides and myomodulins, modulate contraction amplitude and relaxation rate in the accessory radula closer (ARC) muscle of the marine mollusc Aplysia californica. An approximately 750-kDa phosphoprotein was identified in the ARC muscle as the major substrate for cAPK activated either by application of neuropeptides or by peptides released by motorneuron stimulation at physiological frequencies. Immunoblot and immunoelectron microscopy experiments revealed the widespread presence of this protein in Aplysia muscles and its colocalization with contractile filaments in the ARC muscle. Sequence analysis of proteolytic peptide fragments derived from the protein indicated that it is structurally related to the muscle protein twitchin. Finally, the level of neuropeptide-induced phosphorylation of the protein correlated well with peptidergic modulation of the relaxation rate of the muscle. We propose that twitchin in Aplysia, and perhaps in other species, may mediate the modulation of the relaxation rate of muscle contractions.
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PMID:cAMP-dependent phosphorylation of Aplysia twitchin may mediate modulation of muscle contractions by neuropeptide cotransmitters. 807 8

cAMP-dependent protein kinase (PKA) is an important participant in neuronal modulation: the ability of neurons to change their properties in response to external stimuli. In Aplysia mechanosensory neurons, PKA plays roles in both short and long term presynaptic facilitation, which is a simple model for learning and memory. PKA in Aplysia is a collection of structurally and functionally diverse regulatory and catalytic (C) subunits. We have argued that this diversity may in part account for the ability of the enzyme to take part in neuronal events that are spatially and temporally separated. Here, we add credence to this hypothesis by showing that C subunits of Aplysia PKA with alternative N termini target different substrates in subcellular fractions from Aplysia neurons, despite their similar actions on synthetic peptide substrates. Purified recombinant CAPL-AN1A1, which has an N terminus that is homologous to the myristylated sequence described in mammals, catalyzes the formation of two phosphoproteins of 24 and 8 kDa more rapidly than CAPL-AN2A1, which has a distinct N terminus weakly related to that of the yeast TPK1 gene product. The 24-kDa phospoprotein, but not the 8-kDa species, is detected in taxol-stabilized microtubules, suggesting that it is associated with the cytoskeleton. CAPL-AN2A1, in contrast, generates a 55-kDa phosphoprotein that is not observed with CAPL-AN1A1. The 55-kDa species is found in the detergent supernatant of the cytoskeleton fraction. Differential targeting of substrates by C subunits of PKA may therefore contribute to the ability of this kinase to play multiple roles in neuronal modulation.
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PMID:Differential phosphorylation of neuronal substrates by catalytic subunits of Aplysia cAMP-dependent protein kinase with alternative N termini. 808 43

In Aplysia, behavioral sensitization of defensive reflexes and the underlying presynaptic facilitation of sensory-to-motor neuron synapses lasts for several minutes (short term) or days to weeks (long term). Short-term sensitization has been explained by modulation of ion-channel function through cAMP-dependent protein phosphorylation. Long-term facilitation requires additional molecular changes including protein synthesis. A key event is the persistent activation of the cAMP-dependent protein kinase at baseline concentrations of cAMP. This activation is due to selective loss of regulatory (R) subunits of PKA without any change in catalytic (C) subunits. To understand the molecular mechanisms that produce the loss of R subunits in long-term facilitation, we investigated how R subunits are degraded in extracts of Aplysia nervous tissue and in rabbit reticulocyte lysates. Degradation of Aplysia R subunits requires ATP, ubiquitin, and a particulate component that appears to be the proteasome complex. Degradation is blocked by hemin, which causes the accumulation of high molecular weight derivatives of R subunits that are likely to be ubiquitin conjugates of R subunits and intermediates in the degradative pathway. We also show that vertebrate RI and RII subunits can be degraded through the ubiquitin pathway. We suggest that degradation is initiated by cAMP, which causes the holoenzyme to dissociate and, further, that the altered R-to-C ratio in Aplysia sensory neurons is maintained in long-term facilitation by newly synthesized proteins that help target R subunits for accelerated degradation.
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PMID:Regulatory subunits of cAMP-dependent protein kinases are degraded after conjugation to ubiquitin: a molecular mechanism underlying long-term synaptic plasticity. 839 48


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