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)

Cholinergic interneurons have been implicated in striatally mediated associative learning. In classical conditioning paradigms, conditioned stimuli trigger a transient suppression of neuronal activity that is dependent upon an intact dopaminergic innervation. Our hypothesis was that this suppression reflected dopaminergic enhancement of sensory-linked GABAergic input. As a test, the impact of dopamine on interneuronal GABA(A) receptor function was studied by combined patch-clamp recording and single-cell reverse transcription PCR. Activation of D5 dopamine receptors reversibly enhanced a Zn2+-sensitive component of GABA(A) currents. Although dependent upon protein kinase A (PKA) activation, the modulation was blocked by protein phosphatase 1 (PP1) inhibition, suggesting it was dependent upon dephosphorylation. These results establish a novel mechanism by which intrastriatally released dopamine mediates changes in GABAergic signaling that could underlie the initial stages of associative learning.
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PMID:D5 dopamine receptors enhance Zn2+-sensitive GABA(A) currents in striatal cholinergic interneurons through a PKA/PP1 cascade. 939 May 24

Run-down of GABA activated Cl- currents was found when rat cerebellar granule cells in culture were studied by the whole-cell patch-clamp technique in the absence of ATP in the pipette medium. This event could be prevented, even in the absence of ATP, by using the perforated-patch technique or by adding to the pipette medium either a blocker of protein tyrosine phosphatase, sodium vanadate, or deltamethrin, a blocker of the protein serine/threonine phosphatase calcineurin. Conversely, run-down could be partially induced, even in the presence of ATP, by blockers of tyrosine kinases. A reduction of GABA(A) receptor activity was also found in outside-out membrane patches when ATP was not on the membrane inside. The run-down phenomenon involved all three conductance levels found in these patches: 11, 20 and 30 pS. In all three cases it was due to a reduction of channels' open probability. The single-channel experiments showed that also in this case run-down was prevented by either sodium vanadate or deltamethrin on the membrane cytoplasmic side. Overall, through relatively unphysiological conditions (cells in culture and patch-clamp techniques), the study of the run-down phenomenon shows that the tyrosine phosphorylation state of GABA(A) receptors is of importance in maintaining it in a proper functional state. The data also show that tyrosine phosphorylation state is controlled by a protein tyrosine phosphatase, whose activity in turn is blocked via serine/threonine phosphorylation.
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PMID:Involvement of phosphatase activities in the run-down of GABA(A) receptor function in rat cerebellar granule cells in culture. 953 23

We recently discovered that CO2/H+-sensitive neurons in the ventral medullary surface (VMS) are immunoreactive to glutamate, glutamic acid decarboxylase (GAD), calcineurin and cAMP. We then tested the hypothesis that glutamate, GABA, calcineurin and cAMP affect the activity of CO2/H+-sensitive neurons in the VMS. Using male Wistar rats anesthetized with urethane and pentobarbital, we checked for changes in relative tidal volume (VT) and respiratory frequency (f) in response to injecting the VMS with a variety of test agents dissolved in mock CSF. Respiratory changes occurred immediately and were dose-dependent. (1) 200-1600 pmol Glutamate increased VT but decreased f. The glutamate effect was never abolished by concomitant injection of AP5, a NMDA receptor antagonist, but was abolished by CNQX, an AMPA receptor antagonist, indicating predominance of AMPA receptors in the CO2/H+-sensitive neurons in the VMS. (2) 200-1600 pmol GABA decreased both VT and f. The GABA effect was never abolished by concomitant injection of saclofen, a GABA(B) receptor antagonist, but was abolished by bicuculline, a GABA(A) receptor antagonist, indicating predominance of GABA(A) receptors in the CO2/H+-sensitive neurons in the VMS. (3) 4-32 microg Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase 2B, and 200-1600 pmol FK506, selective inhibitor of calcineurin, had no effect on respiration when they were applied extracellularly, but 400-3200 pmol BAPTA-AM, an intracellular Ca2+-chelating agent, decreased both VT and f, indicating involvement of intracellular Ca2+ in the excitatory mechanisms of respiration. (4) 100-800 pmol IBMX, an enhancer of intracellular cAMP, decreased both VT and f, indicating involvement of cAMP in the inhibitory mechanisms of respiration. These results indicate that the CO2/H+-sensitive neurons in the VMS contain glutamate and/or GABA in cytoplasma, possess AMPA and/or GABA(A) receptors on surface of plasma membrane, and compose the internal circuit, and that their activities are regulated by Ca2+ and cAMP.
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PMID:Pharmacological properties of the CO2/H+-sensitive area in the ventral medullary surface assessed by the effects of chemical stimulation on respiration. 976 77

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

The GABA(A) receptor and the non-NMDA subtype of the ionotropic glutamate receptor were co-expressed in Xenopus oocytes by injection of quail brain mRNA. The oocytes were treated with various protein kinase (PK) and protein phosphatase (PP) activators and inhibitors and the effects on receptor functioning were monitored. Two phorbol esters, 4-beta-phorbol 12-myristate-13-acetate (PMA) and 4-beta-phorbol 12,13-dibutyrate (PDBu); the cGMP-dependent PK activators sodium nitroprusside (SNP) and S-nitrosoglutathione (SNOG); and the PP inhibitor okadaic acid (OA) reduced the amplitude of the GABA-induced currents, whilst the PK inhibitor staurosporine potentiated it. In addition, PMA, PDBu, SNP, and OA reduced the desensitization of the GABA-induced response. Identical treatments generally had similar but less pronounced effects on responses generated by kainate (KA) but the desensitization characteristic of the non-NMDA receptor was not affected. None of the treatments had any effect on the reversal potentials of the induced currents. Immunoblots revealed that the oocytes express endogenous PKG and guanylate cyclase. The results are discussed in terms of the molecular structures of GABA(A) and non-NMDA receptors and the potential functional consequences of phosphorylation/dephosphorylation.
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PMID:Protein kinase and phosphatase modulation of quail brain GABA(A) and non-NMDA receptors co-expressed in Xenopus oocytes. 1067 79

Dopamine is a critical determinant of neostriatal function, but its impact on intrastriatal GABAergic signaling is poorly understood. The role of D(1) dopamine receptors in the regulation of postsynaptic GABA(A) receptors was characterized using whole cell voltage-clamp recordings in acutely isolated, rat neostriatal medium spiny neurons. Exogenous application of GABA evoked a rapidly desensitizing current that was blocked by bicuculline. Application of the D(1) dopamine receptor agonist SKF 81297 reduced GABA-evoked currents in most medium spiny neurons. The D(1) dopamine receptor antagonist SCH 23390 blocked the effect of SKF 81297. Membrane-permeant cAMP analogues mimicked the effect of D(1) dopamine receptor stimulation, whereas an inhibitor of protein kinase A (PKA; Rp-8-chloroadenosine 3',5' cyclic monophosphothioate) attenuated the response to D(1) dopamine receptor stimulation or cAMP analogues. Inhibitors of protein phosphatase 1/2A potentiated the modulation by cAMP analogues. Single-cell RT-PCR profiling revealed consistent expression of mRNA for the beta1 subunit of the GABA(A) receptor-a known substrate of PKA-in medium spiny neurons. Immunoprecipitation assays of radiolabeled proteins revealed that D(1) dopamine receptor stimulation increased phosphorylation of GABA(A) receptor beta1/beta3 subunits. The D(1) dopamine receptor-induced phosphorylation of beta1/beta3 subunits was attenuated significantly in neostriata from DARPP-32 mutants. Voltage-clamp recordings corroborated these results, revealing that the efficacy of the D(1) dopamine receptor modulation of GABA(A) currents was reduced in DARPP-32-deficient medium spiny neurons. These results argue that D(1) dopamine receptor stimulation in neostriatal medium spiny neurons reduces postsynaptic GABA(A) receptor currents by activating a PKA/DARPP-32/protein phosphatase 1 signaling cascade targeting GABA(A) receptor beta1 subunits.
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PMID:D(1) dopamine receptor activation reduces GABA(A) receptor currents in neostriatal neurons through a PKA/DARPP-32/PP1 signaling cascade. 1080 95

The inhibitory GABA(A) receptor is a key element in determining the pattern of nerve cell electrical activity. Thus, modulation of its function is of paramount impact in shaping neuronal functional activity under physiological and pathological conditions. This applies to cerebellar granule neurons as to all the other neurons in the brain. The culture of cerebellar granules from newborn rats is a convenient means by which to approach these cells for electrophysiological studies provided that they maintain, as far as GABA(A) receptors are concerned, the same characteristics as in situ. Thus, the regulation of GABA(A) receptor activity in these neurons has been studied by the patch-clamp technique, both in the whole-cell and outside-out configuration. An obvious first level of control of such receptors' activity is their desensitization under continued agonist application, with biphasic kinetics. The data do not allow one to conclude whether one is dealing with two different populations of receptors or with a single population with two desensitization phases; although the presence of two GABA(A) receptor populations is suggested by a host of observations. The granule cell GABA(A) receptors are modulated by changes in extracellular pH with lower pH resulting in an enhanced receptor activity. They display, under the conditions of whole-cell recording, a run-down phenomenon which is most probably due to a tyrosine phosphatase activity which is in turn under control by a protein serine kinase. Thus, in situ tyrosine phosphorylation is a key element in determining the efficiency of GABA mediated inhibition. Activation of protein kinase A or protein kinase G (PKG) down-regulates GABA(A) receptors' activity. This last event is involved in the depression of those receptors' activity by L-arginine via the production of nitric oxide. In addition, the activity of calmodulin-activated adenylate cyclase I is controlled by GABA(B) receptors. Dendritic GABA(A) receptor activity is partially blocked by previous activation of N-methyl-D-aspartate (NMDA) receptors via calcineurin mediated dephosphorylation/activation of protein tyrosine phosphatase and concomitant production of nitric oxide and PKG activation. The site phosphorylated by PKG is evidently not available for calcineurin-mediated serine dephosphorylation, due to calcineurin-specific membrane localization in respect of the GABA(A) receptor. Overall, a complex network of biochemical signals appear to keep granule cells GABA(A) receptors under a fine balance between up- and down-regulatory mechanisms. The overall data appear also to indicate the presence of two GABA(A) receptor populations: a dendritic one which can be modulated by Ca++ entering via NMDA receptors and a cell body one. The two populations are probably different in terms of desensitization kinetics and benzodiazepine sensitivity.
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PMID:GABA(A) receptor modulation in rat cerebellum granule cells. 1095 91

Synaptic plasticity, a cellular basis of learning and memory, has been studied extensively at excitatory synapses. Although synaptic plasticity has also been reported at inhibitory synapses, the molecular mechanism remains elusive. Here we attempted to clarify the overall signaling cascades regulating the induction of inhibitory synaptic plasticity in the cerebellum. Rebound potentiation (RP), a long-lasting increase in GABA(A) receptor (GABA(A)R) responsiveness, is induced by postsynaptic depolarization of a Purkinje neuron (PN) at synapses formed with inhibitory interneurons (stellate or basket neurons). Previously, we showed that RP is suppressed by homosynaptic activation during depolarization through activation of the postsynaptic GABA(B) receptor (GABA(B)R). Activation of GABA(B)R reduces cAMP-dependent protein kinase (PKA) activity via the G(i)/G(o)-protein. Here we examined the molecular pathway through which PKA activity affects RP induction. We confirmed that inhibition of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) or PKA suppresses RP. We also found that inhibition of protein phosphatase 1 (PP-1) or calcineurin (PP-2B) impaired suppression of RP induction. Inhibition of either PP-1 or calcineurin abolished RP impairment by PKA inhibition, but not that by CaMKII inhibition. Antisense oligonucleotide-mediated knock down of DARPP-32, which is a substrate of PKA and calcineurin and inhibits PP-1 when phosphorylated by PKA, suppressed RP. Furthermore, activation of GABA(B)R inhibited CaMKII activation through PKA inhibition and PP-1 activity. These results suggest that calcineurin activation accompanied by PKA inhibition in a PN causes dephosphorylation of DARPP-32, which releases PP-1 from inhibition. PP-1 in turn inhibits CaMKII activity, which is then directly involved in the RP induction.
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PMID:Signaling cascade regulating long-term potentiation of GABA(A) receptor responsiveness in cerebellar Purkinje neurons. 1201 16

Dopaminergic neurotransmission in the prefrontal cortex (PFC) plays an important role in regulating cognitive processes and emotional status. The dopamine D4 receptor, which is highly enriched in the PFC, is one of the principal targets of antipsychotic drugs. To understand the cellular mechanisms and functional implications of D4 receptors, we examined the impact of D4 receptors in PFC pyramidal neurons on GABAergic inhibition, a key element in the regulation of "working memory." Application of the D4 agonist N-(methyl)-4-(2-cyanophenyl)piperazinyl-3-methylbenzamide maleate caused a reversible decrease in postsynaptic GABA(A) receptor currents; this effect was blocked by the D4 antagonist 3-[(4-[4-chlorophenyl]piperazine-1-yl)methyl]-[1H]-pyrrolo[2,3-b]pyridine but not by the D2 antagonist sulpiride, suggesting mediation by D4 receptors. Application of PD168077 also reduced the GABA(A) receptor-mediated miniature IPSC amplitude in PFC pyramidal neurons recorded from slices. The D4 modulation of GABA(A) receptor currents was blocked by protein kinase A (PKA) activation and occluded by PKA inhibition. Inhibiting the catalytic activity of protein phosphatase 1 (PP1) also eliminated the effect of PD168077 on GABA(A) currents. Furthermore, disrupting the association of the PKA/PP1 complex with its scaffold protein Yotiao significantly attenuated the D4 modulation of GABA(A) currents, suggesting that Yotiao-mediated targeting of PKA/PP1 to the vicinity of GABA(A) receptors is required for the dopaminergic signaling. Together, our results show that activation of D4 receptors in PFC pyramidal neurons inhibits GABA(A) channel functions by regulating the PKA/PP1 signaling complex, which could underlie the D4 modulation of PFC neuronal activity and the actions of antipsychotic drugs.
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PMID:Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex. 1241 43

Long-term depression (LTD) is an activity-dependent weakening of synaptic efficacy at individual inhibitory synapses, a possible cellular model of learning and memory. Here, we show that the induction of LTD of inhibitory transmission recruits activated calcineurin (CaN) to dephosphorylate type-A GABA receptor (GABA(A)Rs) via the direct binding of CaN catalytic domain to the second intracellular domain of the GABA(A)R-gamma(2) subunits. Prevention of the CaN-GABA(A) receptor complex formation by expression of an autoinhibitory domain of CaN in the hippocampus of transgenic mice blocks the induction of LTD. Conversely, genetic expression of the CaN catalytic domain in the hippocampus depresses inhibitory synaptic responses, occluding LTD. Thus, an activity-dependent physical and functional interaction between CaN and GABA(A) receptors is both necessary and sufficient for inducing LTD at CA1 individual inhibitory synapses.
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PMID:Interaction of calcineurin and type-A GABA receptor gamma 2 subunits produces long-term depression at CA1 inhibitory synapses. 1257 11


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