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)

The transcription factor CREB is involved in mediating many of the long-term effects of activity-dependent plasticity at glutamatergic synapses. Here, we show that activation of NMDA receptors and voltage-sensitive calcium channels leads to CREB-mediated transcription in cortical neurons via a mechanism regulated by CREB-binding protein (CBP). Recruitment of CBP to the promoter is not sufficient for transactivation, but calcium influx can induce CBP-mediated transcription via two distinct transactivation domains. CBP-mediated transcription is stimulus strength-dependent and can be induced by activation of CaM kinase II, CaM kinase IV, and protein kinase A, but not by activation of the Ras-MAP kinase pathway. These observations indicate that CBP can function as a calcium-sensitive transcriptional coactivator that may act as a regulatory switch for glutamate-induced CREB-mediated transcription.
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PMID:Regulation of CBP-mediated transcription by neuronal calcium signaling. 1023 Jul 99

Perfusion of hippocampal slices with an inhibitor nitric oxide (NO) synthase blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.
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PMID:On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus. 1048 62

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

The nucleus accumbens and its associated circuitry subserve behaviors linked to natural or biological rewards, such as feeding, drinking, sex, exploration, and appetitive learning. We have investigated the functional role of neurotransmitter and intracellular transduction mechanisms in behaviors subserved by the core and shell subsystems within the accumbens. Local infusion of the selective NMDA antagonist, AP-5, into the accumbens core, but not the shell, completely blocked acquisition of a bar-press response for food in hungry rats. This effect was apparent only when infused during the early stages of learning. We have also recently shown that infusion of certain protein kinase inhibitors into the core also impairs learning in the same paradigm. These results suggest that plasticity-related mechanisms within the accumbens core, involving glutamate-linked intracellular second messengers, are important for response-reinforcement learning. In contrast to the core, which primarily connects to somatic motor output systems, the shell is more intimately linked to viscero-endocrine effector systems. We have shown that both AMPA and GABA receptors within the medial shell (but not the core) are critically involved in controlling the brain's feeding pathways, via activation of the lateral hypothalamus (LH). This effect is blocked by local inhibition of the LH in double-cannulae experiments and also strongly and selectively activates Fos expression in the LH. These results provide a newly emerging picture of the differentiated functions of this forebrain region and suggest an integrated role in the elaboration of adaptive motor actions.
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PMID:Functional specificity of ventral striatal compartments in appetitive behaviors. 1041 44

Previous results have suggested that cGMP is involved in hippocampal long-term potentiation (LTP), perhaps as the presynaptic effector of a retrograde messenger. However, other studies have failed to replicate some of those results, making the role of cGMP uncertain. We therefore reexamined this question and identified several variables that can affect the contribution of cGMP. First, brief perfusion with 8-Br-cGMP before weak tetanic stimulation produced long-lasting potentiation in the CA1 region of hippocampal slices, but more prolonged perfusion with 8-Br-cGMP before the tetanus did not produce long-lasting potentiation. Second, the activity-dependent long-lasting potentiation by cGMP analogs was reduced when NMDA receptors were completely blocked, indicating that NMDA receptor activation contributes to, but is not required for, the potentiation. The amount of reduction of the potentiation differed with different protocols, and in some cases could be complete. Third, LTP produced by strong tetanic stimulation in the stratum radiatum of CA1 (which expresses eNOS) was blocked by inhibitors of soluble guanylyl cyclase or cGMP-dependent protein kinase, but LTP in the stratum oriens (which does not express eNOS) was not. The results of these experiments should help to explain some of the discrepant findings from previous studies, and, in addition, may provide insights into the mechanisms and functional role of the cGMP-dependent component of LTP.
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PMID:The specific role of cGMP in hippocampal LTP. 1045 67

Perfusion of hippocampal slices with an inhibitor of nitric oxide (NO) synthase-blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.
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PMID:On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus. 1035 25

Application of brain-derived neurotrophic factor (BDNF) to hippocampal neurons has profound effects on glutamatergic synaptic transmission. Both pre- and postsynaptic actions have been identified that depend on the age and type of preparation. To understand the nature of this diversity, we have begun to examine the mechanisms of BDNF action in cultured dissociated embryonic hippocampal neurons. Whole-cell patch-clamp recording during iontophoretic application of glutamate revealed that BDNF doubled the amplitude of induced inward current. Coexposure to BDNF and the NMDA receptor antagonist AP-5 markedly reduced, but did not entirely prevent, the increase in current. Coexposure to BDNF and ifenprodil, an NR2B subunit antagonist, reproduced the response observed with AP-5, suggesting BDNF primarily enhanced activity of NR2B-containing NMDA receptors with a lesser effect on non-NMDA receptors. Protein kinase involvement was confirmed with the broad spectrum inhibitor staurosporine, which prevented the response to BDNF. PKCI19-31 and H-89, selective antagonists of PKC and PKA, had no effect on the response to BDNF, whereas autocamtide-2-related inhibitory peptide, an antagonist of CaM kinase II, reduced response magnitude by 60%. These results demonstrate the predominant role of a specific NMDA receptor subtype in BDNF modulation of hippocampal synaptic transmission.
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PMID:Blockade of NR2B-containing NMDA receptors prevents BDNF enhancement of glutamatergic transmission in hippocampal neurons. 1049 7

NMDA currents from Xenopus oocytes expressing recombinant zeta1/epsilon2 NMDA receptors can be potentiated by activation of protein kinase-C (PKC) and also demonstrate time-dependent rundown. In order to determine whether cytoskeletal proteins are involved in either of these phenomena, experiments were performed using the f-actin stabilizer phalloidin, the f-actin de-stabilizer cytochalasin-D, and the microtubule stabilizer taxol. Phalloidin treatment both prevented rundown and inhibited PKC-potentiation of whole-cell currents but did not affect baseline current amplitudes. Treatment with cytochalasin-D also prevented rundown and inhibited PKC-potentiation of whole-cell currents, but baseline currents from cytochalasin treated cells were only 50% as large as those from control cells. Taxol had no effect on either rundown or PKC potentiation of NMDA currents. The results indicate that both spontaneous rundown and PKC potentiation of currents from heterologously expressed zeta1/epsilon2 NMDA receptors depend on dynamic actin polymerization/depolymerization but do not involve changes in microtubules.
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PMID:Protein kinase C potentiation of currents from mouse zeta1/epsilon2 NMDA receptors expressed in Xenopus oocytes depends on f-actin/g-actin cycling. 1050 12

Hydrogen sulfide (H(2)S) is produced endogenously from l-cysteine in mammalian tissues, and may function as a neuromodulator in the brain as well as a tone regulator in smooth muscle. H(2)S is present at relatively high levels in the brain, and cystathionine beta-synthase (CBS), which is highly expressed in the hippocampus, is involved in the production of brain H(2)S. Physiological concentrations of H(2)S selectively enhance NMDA receptor-mediated currents and facilitate the induction of hippocampal long-term potentiation (LTP). The NMDA receptor subunits are directly phosphorylated at specific sites by protein kinase A (PKA), resulting in the activation of NMDA-receptor-mediated excitatory postsynaptic currents. PKA activation is also observed in the induction of LTP. Here we show that physiological concentrations of H(2)S increase the production of cAMP in primary cultures of brain cells, neuronal and glial cell lines, and Xenopus oocytes. NMDA receptors expressed on Xenopus oocyte membrane are modulated by H(2)S. This modulation by H(2)S is specifically inhibited by adenylyl cyclase-specific inhibitor MDL-12, 330A. The present findings provide a mechanism for the previous observation that H(2)S modulates NMDA receptors and enhances the induction of LTP.
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PMID:Hydrogen sulfide induces cyclic AMP and modulates the NMDA receptor. 1062 86

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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