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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypothetical mechanism of homo-, hetero-, and associative LTD in the efficacy of excitatory synaptic transmission is suggested. According to this hypothesis, the same mechanisms underlie these effects. It is proposed that the following conditions are necessary and sufficient to produce different types of LTD. Conditioning and test stimuli must activate the common inhibitory neuron which is presynaptic to the target cell. The postsynaptic Ca2+ concentration which is regulated by metabotropic mGlu and GABAb receptor activation and opening of voltage-dependent Ca2+ channels must exceed a certain moderate level. This leads to an increase in protein phosphatase and decrease in protein kinases concentrations and cause dephosphorylation of ionotropic AMPA, NMDA, and GABAa receptors. Dephosphorylation results in a decrease of the sensitivity of excitatory and increase in the sensitivity of inhibitory receptors and causes simultaneous LTD excitatory and LTP of inhibitory synaptic transmission.
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PMID:[The simultaneous activation of excitatory and inhibitory inputs as a condition for the induction of homo-, hetero- and associative long-term excitation depression]. 858 5

The computational model was put forward of calcium-dependent posttetanic processes in the dendritic spine of CA3 hippocampal pyramidal neuron which received excitatory and inhibitory afferents. The system of differential equations enables description and evaluation of changes in protein kinase and protein phosphatase activity induced by changes in postsynaptic Ca2+ ion concentration (Cap2+). It was shown that the synaptic efficacy is determined by the ratio between active protein kinases and active protein phosphatase I. According to the proposed model, increase/decrease in Cap2+ concentration relative to the Cap2+ rise, produced by prior stimulation, results in the increase/decrease in the number of phosphorylated ionotropic receptors and in LTP/LTD synaptic efficacy. It follows form the model calculations that the same mechanisms underlie the LTP, LTD, and depotentiation. Some results of experimental study of the hippocampal and neocortical synaptic plasticity are explained and systematized.
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PMID:[The mathematical modelling of Ca2(+)-dependent postsynaptic processes in the hippocampus (the induction of long-term potentiation and long-term depression)]. 898 6

The studies discussed in this review demonstrate that phosphorylation is an important mechanism for the regulation of ligand-gated ion channels. Structurally, ligand-gated ion channels are heteromeric proteins comprised of homologous subunits. For both the AChR and the GABA(A) receptor, each subunit has a large extracellular N-terminal domain, four transmembrane domains, a large intracellular loop between transmembrane domains M3 and M4, and an extracellular C-terminal domain (Fig. 1B). All the phosphorylation sites on these receptors have been mapped to the major intracellular loop between M3 and M4 (Table 1). In contrast, glutamate receptors appear to have a very large extracellular N-terminal domain, one membrane hairpin loop, three transmembrane domains, a large extracellular loop between transmembrane domains M3 and M4, and an intracellular C-terminal domain (Fig. 1C). Most phosphorylation sites on glutamate receptors have been shown to be on the intracellular C-terminal domain, although some have been suggested to be on the putative extracellular loop between M3 and M4 (Table 1). A variety of extracellular factors and intracellular signal transduction cascades are involved in regulating phosphorylation of these ligand-gated ion channels (Fig. 2). Once again, the AChR at the neuromuscular junction is the most fully understood system. Phosphorylation of the AChR by PKA is stimulated synaptically by the neuropeptide CGRP and in an autocrine fashion by adenosine released from the muscle in response to acetylcholine. In addition, acetylcholine, via calcium influx through the AChR, appears to activate calcium-dependent kinases including PKC to stimulate serine phosphorylation of the receptor. Presently, agrin is the only extracellular factor known to stimulate phosphorylation of the AChR on tyrosine residues. For glutamate receptors, non-NMDA receptor phosphorylation by PKA is stimulated by dopamine, while NMDA receptor phosphorylation by PKA and PKC can be induced via the activation of beta-adrenergic receptors, and metabotropic glutamate or opioid receptors, respectively. In addition, Ca2+ influx through the NMDA receptor has been shown to activate PKC. CaMKII, and calcineurin, resulting in phosphorylation of AMPA receptors (by CaMKII) and inactivation of NMDA receptors (at least in part through calcineurin). In contrast to the AChR and glutamate receptors, no information is presently available regarding the identities of the extracellular factors and intracellular signal transduction cascades that regulate phosphorylation of the GABA(A) receptor. Surely, future studies will be aimed at further clarifying the molecular mechanisms by which the central receptors are regulated. The presently understood functional effects of ligand-gated ion channel phosphorylation are diverse. At the neuromuscular junction, a regulation of the AChR desensitization rate by both serine and tyrosine phosphorylation has been demonstrated. In addition, tyrosine phosphorylation of the AChR or other synaptic components appears to play a role in AChR clustering during synaptogenesis. For the GABA(A) receptor, the data are complex. Both activation and inhibition of GABA(A) receptor currents as a result of PKA and PKC phosphorylation have been reported, while phosphorylation by PTK enhances function. The predominant effect of glutamate receptor phosphorylation by a variety of kinases is a potentiation of the peak current response. However, PKC also modulates clustering of NMDA receptors. This complexity in the regulation of ligand-gated ion channels by phosphorylation provides diverse mechanisms for mediating synaptic plasticity. In fact, accumulating evidence supports the involvement of protein phosphorylation and dephosphorylation of AMPA receptors in LTP and LTD respectively. There has been a dramatic increase in our understanding of the nature by which phosphorylation regulates ligand-gated ion channels. However, many questions remain unanswered. (AB
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PMID:Regulation of ligand-gated ion channels by protein phosphorylation. 1021 14

Calcineurin is ubiquitously distributed phosphatase in the central nervous system. It has various functions, such as modulating channel properties, suppressing transmitter release, and activating transcript factors. Recently the critical role of calcineurin on synaptic plasticity, especially long-term depression, was reported, although the precise mechanism underlying LTD induction is still being debated. Calcineurin, activated by the Ca2+ influx mainly through the NMDA channel and calmodulin, dephosphorylates inhibitor-1, which suppresses PP1 activity. Thus the activation of calcineurin enhances PP1, resulting in facilitating the process leading to LTD induction. The activation of calcineurin modifies the threshold of LTP induction. A recent interesting finding is the gating mechanism from the early phase of LTP to the late phase of LTP by calcineurin activity, a process regulated by cAMP. We have reported a new type of LTD, which is suppressed by calcineurin that is dependent on group 2 mGluR receptor activity. According to the result using whole cell study with a patch pipette, including FK-506, an antagonist of calcineurin, the induction site of this LTD is presynaptic, which defers from conventional LTD. We have also discussed the involvement of murine protein tyrosine phosphatase (MPTP) in LTD induction in the hippocampal CA1 region by using an MPTP delta knockout mouse.
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PMID:[The role of calcineurin on the induction of synaptic plasticity]. 1132 44

Calcineurin is a calcium-dependent protein phosphatase that has been implicated in various aspects of synaptic plasticity. By using conditional gene-targeting techniques, we created mice in which calcineurin activity is disrupted specifically in the adult forebrain. At hippocampal Schaffer collateral-CA1 synapses, LTD was significantly diminished, and there was a significant shift in the LTD/LTP modification threshold in mutant mice. Strikingly, although performance was normal in hippocampus-dependent reference memory tasks, including contextual fear conditioning and the Morris water maze, the mutant mice were impaired in hippocampus-dependent working and episodic-like memory tasks, including the delayed matching-to-place task and the radial maze task. Our results define a critical role for calcineurin in bidirectional synaptic plasticity and suggest a novel mechanistic distinction between working/episodic-like memory and reference memory.
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PMID:Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. 1173 61

NMDAR-dependent long-term depression involves the activation of protein phosphatase 1 (PP1) and 2B (calcineurin) and the subsequent dephosphorylation of synaptic proteins. In this issue of Neuron, Morishita et al. (2001) provide evidence that precise targeting of PP1 to synaptic substrates is critical for the expression of LTD.
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PMID:Protein phosphatase 1 and LTD: synapses are the architects of depression. 1175 43

We investigated the role of postsynaptic protein phosphatase 1 (PP1) in regulating synaptic strength by loading CA1 pyramidal cells either with peptides that disrupt PP1 binding to synaptic targeting proteins or with active PP1. The peptides blocked synaptically evoked LTD but had no effect on basal synaptic currents mediated by either AMPA or NMDA receptors. They did, however, cause an increase in synaptic strength following the induction of LTD. Similarly, PP1 had no effect on basal synaptic strength but enhanced LTD. In cultured neurons, synaptic activation of NMDA receptors increased the proportion of PP1 localized to synapses. These results suggest that PP1 does not significantly regulate basal synaptic strength. Appropriate NMDA receptor activation, however, allows PP1 to gain access to synaptic substrates and be recruited to synapses where its activity is necessary for sustaining LTD.
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PMID:Regulation of synaptic strength by protein phosphatase 1. 1175 28

Aging is associated with an impaired ability to maintain long-term potentiation (LTP), but the underlying cause of the impairment remains unclear. To gain a better understanding of the cellular and molecular mechanisms responsible for this impairment, the synaptic transmission and plasticity were studied in the CA1 region of hippocampal slices from adult (6-8 months) and poor-memory (PM)-aged (23-24 months) rats. The one-way inhibitory avoidance learning task was used as the behavioral paradigm to screen PM-aged rats. With intracellular recordings, CA1 neurons of PM-aged rats exhibited a more hyperpolarized resting membrane potential, reduced input resistance, and increased amplitude of afterhyperpolarization and spike threshold, compared with those in adult rats. Although a reduction in the size of excitatory synaptic response was observed in PM-aged rats, no obvious differences were found between adult and PM-aged rats in the pharmacological properties of excitatory synaptic response, paired-pulse facilitation, or frequency-dependent facilitation, which was tested with trains of 10 pulses at 1, 5, and 10 Hz. Slices from the PM-aged rats displayed significantly reduced early-phase long-term potentiation (E-LTP) and late-phase LTP (L-LTP), and the entire frequency-response curve of LTP and LTD is modified to favor LTD induction. The susceptibility of time-dependent reversal of LTP by low-frequency afferent stimulation was also facilitated in PM-aged rats. Bath application of the protein phosphatase inhibitor, calyculin A, enhanced synaptic response in slices from PM-aged, but not adult, rats. In contrast, application of the cAMP-dependent protein kinase inhibitors, Rp-8-CPT-cAMPS and KT5720, induced a decrease in synaptic transmission only in slices from the adult rats. Furthermore, the selective beta-adrenergic receptor agonist, isoproterenol, and pertussis toxin-sensitive G-protein inhibitor, N-ethylmaleimide, effectively restored the deficit in E-LTP and L-LTP of PM-aged rats. These results demonstrate that age-related impairments of synaptic transmission and LTP may result from alterations in the balance of protein kinase/phosphatase activities.
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PMID:Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation. 1254 30

Postsynaptic Ca2+ signals of different amplitudes and durations are able to induce either long-lasting potentiation (LPT) or depression (LTD). The bidirectional character of synaptic plasticity may result at least in part from an increased or decreased responsiveness of the glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPA-R) due to the modification of conductance and/or channel number, and controlled by the balance between the activities of phosphorylation and dephosphorylation pathways. AMPA-R depression can be induced by a long-lived Ca2+ signal of moderate amplitude favouring the activation of the dephosphorylation pathway, whereas a shorter but higher Ca2+ signal would induce AMPA-R potentiation resulting from the preferential activation of the phosphorylation pathway. Within the framework of a model involving calcium/calmodulin-dependent protein kinase II (CaMKII), calcineurin (PP2B) and type 1 protein phosphatase (PP1), we aimed at delineating the conditions allowing a biphasic U-shaped relationship between AMPA-R and Ca2+ signal amplitude, and thus bidirectional plasticity. Our theoretical analysis shows that such a property may be observed if the phosphorylation pathway: (i) displays higher cooperativity in its Ca2+-dependence than the dephosphorylation pathway; (ii) displays a basal Ca2+-independent activity; or (iii) is directly inhibited by the dephosphorylation pathway. Because the experimentally observed inactivation of CaMKII by PP1 accounts for this latter characteristic, we aimed at verifying whether a realistic model using reported parameters values can simulate the induction of either LTP or LTD, depending on the time and amplitude characteristics of the Ca2+ signal. Our simulations demonstrate that the experimentally observed bidirectional nature of Ca2+-dependent synaptic plasticity could be the consequence of the PP1-mediated inactivation of CaMKII.
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PMID:Bidirectional synaptic plasticity as a consequence of interdependent Ca2+-controlled phosphorylation and dephosphorylation pathways. 1282 59

Recent work has demonstrated that brief application of insulin to hippocampal slices can induce a novel form of long-term depression (insulin-LTD) in the CA1 region of the hippocampus; however, the molecular details of how insulin triggers LTD remain unclear. Using electrophysiological and biochemical approaches in the hippocampal slices, we show here that insulin-LTD (i) is specific to 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor- but not NMDA receptor-mediated synaptic transmission; (ii) is induced and expressed postsynaptically but does not require the activation of ionotropic and metabotropic glutamate receptors; (iii) requires a concomitant Ca(2+) influx through l-type voltage-activated Ca(2+) channels (VACCs) and the release of Ca(2+) from intracellular stores; (iv) requires the series of protein kinases, including protein tyrosine kinase (PTK), phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC); (v) is mechanistically distinct from low-frequency stimulation-induced LTD (LFS-LTD) and independent on protein phosphatase 1/2 A (PP1/2 A) and PP2B activation; (vi) is dependent on a rapamycin-sensitive local translation of dendritic mRNA, and (vii) is associated with a persistent decrease in the surface expression of GluR2 subunit. These results suggest that a PI3K/PKC-dependent insulin signaling, which controls postsynaptic surface AMPA receptor numbers through PP-independent endocytosis, may be a major expression mechanism of insulin-LTD in hippocampal CA1 neurons.
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PMID:An investigation into signal transduction mechanisms involved in insulin-induced long-term depression in the CA1 region of the hippocampus. 1503 Apr 6


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