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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The ionotropic purinoceptors in isolated Deiters' cells of guinea-pig cochlea were characterized by use of the whole-cell variant of the patch-clamp technique. 2. Extracellular application of adenosine 5'-triphosphate (ATP) induced a dose-dependent inward current when the cells were voltage-clamped at -80 mV. The ATP-induced current showed desensitization and had a reversal potential around -4 mV. 3. Increasing intracellular free Ca2+ by decreasing the concentration of EGTA in the pipette solution reduced the amplitude of the ATP-gated current. 4. The order of agonist potency was: 2-methylthioATP (2-meSATP)>ATP>benzoylbenzoyl-ATP (BzATP)>alpha,beta-methyleneATP (alpha,beta,meATP>adenosine 5'-diphosphate (ADP)>uridine 5'-triphosphate (UTP)>adenosine 5'-monophosphate (AMP)=adenosine (Ad). 5. Pretreatment with forskolin (10 microM), 8-bromoadenosine-3',5'-cyclophosphate (8-Br-cyclic AMP, 1 mM), 3-isobutyl-1-methylxanthine (IBMX, 1 mM) or phorbol-12-myristate-13-acetate (PMA, 1 microM) reversibly reduced the ATP-induced peak current. 6. The results are consistent with molecular biological data which indicate that P2X2 purinoceptors are present in Deiters' cells. In addition, the reduction of the ATP-gated current by activators of protein kinase A and protein kinase C indicates that these P2X2 purinoceptors can be functionally modulated by receptor phosphorylation.
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PMID:P2X receptors in cochlear Deiters' cells. 964 51

Diadenosine polyphosphates present at the cytosol can be transported to secretory granules allowing their exocytotic release. Extracellularly, they can act through specific metabotropic or ionotropic receptors, or as analogues of P2X and P2Y nucleotide receptors. The specific ionotropic receptor P4 is present in synaptic terminals, and modulated by protein kinases (PK) A and C and protein phosphatases. Activation of PKA or PKC, directly or through membrane receptors, results in a decrease of affinity or in reduction of the Ca2+ transient respectively. Adenosine and ATP, both products of the extracellular destruction of diadenosine polyphosphates, acting through A1 or P2Y receptors respectively, are important physiological modulators at the P4 receptor.
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PMID:The neurotransmitter role of diadenosine polyphosphates. 967 98

Long-term potentiation (LTP) is a form of synaptic plasticity that has been extensively studied as a putative mechanism underlying learning and memory. A late phase of LTP occurring 3-5 hours after stimulation and depending on transcription, protein synthesis and cyclic-AMP-dependent protein kinase (protein kinase A, or PKA) has been described, but it is not known whether transcription of presynaptic and/or postsynaptic genes is required to support late-phase LTP. Here we show that late-phase LTP can be obtained in rat hippocampal CA1 mini-slices in which the cell bodies of presynaptic Schaffer collateral/commissural fibres are removed. Thus, transcription of presynaptic genes is not necessary to support maintenance of late-phase LTP. The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor is the predominant mediator of the ionotropic response to synaptically released glutamate in the hippocampus and it has been implicated in LTP maintenance. We find that synthesis of AMPA receptor subunits is increased three hours after LTP induction: this effect on the synthesis of the AMPA receptor is blocked by inhibitors of PKA and of transcription. Our results support the idea of a postsynaptic mechanism maintaining late-phase LTP, in which AMPA receptor synthesis is increased as a result of PKA-dependent gene transcription.
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PMID:Maintenance of late-phase LTP is accompanied by PKA-dependent increase in AMPA receptor synthesis. 971 31

Intracellular and patch clamp recording techniques were used to investigate the role of GABA in immature CA3 hippocampal neurons. During the first postnatal week spontaneous GABA release was detected as spontaneous ongoing synaptic potentials (SPSPs) or giant depolarizing potentials (GDPs). GDPs were generated at regular intervals and regulated by ionotropic glutamate receptors (GluRs), whereas SPSPs occurred randomly and were unaffected by ionotropic GluRs. Both GDPs and SPSPs were positively modulated by metabotropic GluRs through cyclic AMP-dependent protein kinase. Moreover GABA controlled its own release through GABAA and GABAB receptors, probably localized on GABAergic nerve terminals. At this developmental stage, GABA depolarized CA3 pyramidal cells through two distinct classes of chloride-permeable receptors: bicuculline sensitive and insensitive, respectively. The bicuculline-insensitive responses were blocked by picrotoxin in a noncompetitive way. Whole-cell GABA currents, recorded in the presence of bicuculline, had a slower desensitization rate and faster recovery from desensitization. In excised outside-out patches, in the presence of bicuculline, GABA activated single-channel currents with conductances of 14, 22, and 31 pS. These values were similar to those obtained when GABA was applied in the absence of bicuculline. Interestingly, GABA responses obtained in the absence of bicuculline, were sensitive to the blocking effect of zinc, whereas bicuculline-resistant responses were almost unaffected by this divalent cation. Expression of different subunits in native receptors (particularly of the alpha and rho type) may account for the functional differences observed in the present experiments. Activation of bicuculline-insensitive receptors would strengthen and prolong the depolarizing action of GABA, thus favoring the entry of calcium through voltage-dependent calcium channels. This calcium signal may be essential in promoting stabilization of synaptic contacts during a critical period of postnatal development.
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PMID:GABA excites immature CA3 pyramidal cells through bicuculline-sensitive and -insensitive chloride-dependent receptors. 977 44

Recent evidence suggests that the transmembrane topology of ionotropic glutamate receptors differs from other members of the ligand-gated ion channel superfamily. However, the structure of the segment linking membrane domains M3 and M4 (the M3-M4 loop) remains controversial. Although various data indicate that this loop is extracellular, other results suggest that serine residues in this segment are sites of phosphorylation and channel modulation by intracellular protein kinases. To reconcile these data, we hypothesized that the M3-M4 loop structure is dynamic and, more specifically, that the portion containing putative phosphorylation sites may be translocated across the membrane to the cytoplasmic side during agonist binding. To test this hypothesis, we mutated Ser 684, a putative cAMP-dependent protein kinase site in the kainate-type glutamate receptor GluR6, to Cys. Results of biochemical and electrophysiological experiments are consistent with Cys 684 being accessible, in the unliganded state, from the extracellular side to modification by a Cys-specific biotinylating reagent followed by streptavidin (SA). Interestingly, our data suggest that this residue becomes inaccessible to the extracellular biotinylating reagent during agonist binding. However, we find it unlikely that Cys 684 undergoes membrane translocation, because the addition of SA to Cys-biotinylated GluR6(S684C) has no effect on peak glutamate-evoked current and only a small effect on macroscopic desensitization. We conclude that residue 684 in GluR6 is extracellular in the receptor-channel's closed, unliganded state and does not cross the membrane after agonist binding. However, an agonist-induced conformational change in the receptor substantially alters accessibility of position 684 to the extracellular environment.
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PMID:Agonist-induced changes in substituted cysteine accessibility reveal dynamic extracellular structure of M3-M4 loop of glutamate receptor GluR6. 988 May 85

Glutamate receptor induced changes in the activity of different phosphorylation systems were measured in hippocampal slices from 12- and 56-day-old rats, by determining the endogenous phosphorylation of 2.5% perchloric acid (PCA) soluble proteins. We identified among these proteins an 85, 80 kDa and the tau protein as specific substrates for protein kinase A (PKA), MARCKS, and neurogranin as specific substrates for protein kinase C (PKC), and prostaglandin-D-synthase as substrate for casein kinase II (CKII). In addition, a 35 kDa protein was phosphorylated by calcium/calmodulin dependent kinase II and protein kinase C and a 21 kDa protein was a substrate for all investigated kinases. The basal endogenous phosphorylation of 2.5% PCA soluble proteins changed during development qualitatively and quantitatively. Thus, the phosphorylation degree of nearly all proteins declines during maturation. Activation of mGluR induced an increased phosphorylation of PKA, PKC, and CKII substrates in hippocampal slices from 12-day-old rats, but in slices of 56-day-old rats only PKA and to a lower extent PKC substrates were affected. In contrast, stimulation of NMDA receptors led to an enhancement of CKII and PKA dependent phosphorylation only in slices of young animals, whereas the endogenous phosphorylation of some proteins in adult slices was actually decreased. These data showing developmental changes in the coupling of metabotropic and ionotropic glutamate receptors to different phosphorylation systems are discussed in the light of altered physiological properties of the mature hippocampus.
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PMID:Age-dependent differences in glutamate-induced phosphorylation systems in rat hippocampal slices. 1022 77

This study is concerned with the transmitter-mediated regulation of the alpha(50 kDa) and beta(60 kDa) subunits of calcium calmodulin dependent protein kinase II (CamKII) in the adult rat retina. The level of antibody binding to the CamKII and the activity of CamKII were found to be increased after intravitreal injection of glutamate. Changes in the levels of the antibody-binding to the subunits of CamKII were observed in different subcellular fractions of the retina with a maximum response observed in crude synaptic membrane fractions. The glutamate mediated increases in CamKII were specific and blocked by 3,5-Dimethyl-1 adamantanamine; 3,5-Dimethylamantadine (Memantine), (+/-) 2-Amino-5-Phosphopentonic (AP-5) and 6-Cyano-7-Nitroquinoxaline-2,3-Dione (CNQX) but not with dl -2-Amino-3-Phosphono-Propionic (AP-3). The results indicate that the retinal neurotransmitter, glutamate, can regulate retinal CamKII activity through ionotropic but not metabotropic glutamate receptors. NMDA-receptors were found to be necessary but insufficient to stimulate CamKII. A model in which cooperative interaction between NMDA and non-NMDA glutamate receptors/ion channels is presented to explain the glutamate stimulated increases in CamKII activity in the retina.
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PMID:Regulation of calcium/calmodulin-dependent protein kinase II in the adult rat retina is mediated by ionotropic glutamate receptors. 1037 34

We investigated long-term potentiation (LTP) at mossy fiber synapses on CA3 pyramidal neurons in the hippocampus. Using Ca2+ imaging techniques, we show here that when postsynaptic Ca2+ was sufficiently buffered so that [Ca2+]i did not rise during synaptic stimulation, the induction of mossy fiber LTP was prevented. In addition, induction of mossy fiber LTP was suppressed by postsynaptic injection of a peptide inhibitor of cAMP-dependent protein kinase. Finally, when ionotropic glutamate receptors were blocked, LTP depended on the postsynaptic release of Ca2+ from internal stores triggered by activation of metabotropic glutamate receptors. These results support the conclusion that mossy fiber LTP and LTP at other hippocampal synapses share a common induction mechanism involving an initial rise in postsynaptic [Ca2+].
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PMID:Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism. 1040 92

The glutamatergic synapse is the key structure in the development of activity-dependent synaptic plasticity in the central nervous system. The analysis of the complex biochemical mechanisms at the basis of the long-term changes in synaptic efficacy have received a tremendous impulse by the observation that the post-synaptic constituents of the synapse can be separated and purified through a simple procedure involving detergent treatment of synaptosomes and differential centrifugation. In this fraction, called post-synaptic density (PSD), the functional interactions of its constituents are preserved. The various subunits of ionotropic glutamate receptors are held in register with the presynaptic active zone through their interaction with linker proteins. N-methyl-D-aspartate (NMDA) subunits NR2A and NR2B, bind to the PSD protein called PSD-95, which in turn binds neuroligins, providing a handle for interacting with neurexin, located in the plasma membrane at the presynaptic active zone. Additional clustering of NMDA receptors is provided through the binding of NRI subunits to the cytoskeletal protein alpha-actinin-2. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate receptors are other important constituents of PSDs and bind to different anchoring proteins. Phosphorylation processes have long been known to modulate NMDA receptor functional activity: the finding that several protein kinases, particularly Ca2+/Calmodulin-dependent protein kinase II and protein tyrosine kinases of the src family, are major constituents of PSDs has allowed to demonstrate that these enzymes are localized in a strategic position of the glutamatergic synapse, so that their activation provides a means for NMDA receptor function regulation upon its activation. The relevance of these mechanisms has been demonstrated in experimental models of pathologies involving deficits in synaptic plasticity, such as in streptozotocin-induced diabetes and in an animal model of prenatal induced ablation of hippocampal neurons. Both animal models display disturbances in long-term potentiation and cognitive deficits, thus providing in vivo models to study pathology related changes in both the structure and the function of the excitatory synapse.
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PMID:Pathophysiological implications of the structural organization of the excitatory synapse. 1044 87

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


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