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)

Voltage-gated A-type potassium channels such as Kv4.2 regulate generation of action potentials and are localized abundantly in the hippocampus and striatum. Phosphorylation consensus sites for various kinases exist within the sequence of the potassium channel subunit Kv4.2, including consensus sites for extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK), protein kinase A (PKA), protein kinase C (PKC), and calcium/calmodulin-dependent kinase II (CaMKII), and kinase assays have shown that particular amino acids of the consensus sites are bonafide phosphorylation sites in vitro. We have developed antibodies recognizing Kv4.2 triply phosphorylated at the three ERK sites as well as two antibodies recognizing singly phosphorylated Kv4.2 channels at the PKA sites (one amino-terminal and one carboxy-terminal). In the present study, we report the development of reliable immunohistochemistry protocols to study the localization of these phosphorylated versions of Kv4.2, as well as total Kv4.2 in the mouse brain. A general description of the areas highlighted by these antibodies includes the hippocampus, amygdala, cortex, and cerebellum. Such areas display robust synaptic plasticity and have been implicated in spatial, associative, and motor learning. Interestingly, in the hippocampus, the antibodies to differentially phosphorylated Kv4.2 channels localize to specific afferent pathways, indicating that the Kv4.2 phosphorylation state may be input specific. For example, the stratum lacunosum moleculare, which receives inputs from the entorhinal cortex via the perforant pathway, displays relatively little ERK-phosphorylated Kv4.2 or PKA carboxy-terminal-phosphorylated Kv4.2. However, this same layer is highlighted by antibodies that recognize Kv4.2 that has been phosphorylated by PKA at the amino terminus. Similarly, of the three antibodies tested, the soma of CA3 neurons are primarily recognized by the ERK triply phosphorylated Kv4.2 antibody, and the mossy fiber inputs to CA3 are primarily recognized by the carboxy-terminal PKA-phosphorylated Kv4.2. This differential phosphorylation is particularly interesting in two contexts. First, phosphorylation may be serving as a mechanism for targeting. For example, the amino-terminal PKA phosphorylation may be acting as a tag for a discrete pool of Kv4.2 to enter stratum lacunosum moleculare. Second, as phosphorylation may regulate channel biophysical properties, differential phosphorylation of Kv4.2 in the dendrites of pyramidal neurons may confer unique biophysical properties upon particular dendritic input layers.
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PMID:Input-specific immunolocalization of differentially phosphorylated Kv4.2 in the mouse brain. 1104 Feb 64

Type 1 inositol 1,4,5-trisphosphate receptors are phosphorylated by cyclic-AMP-dependent protein kinase A at serines 1589 and 1755, with serine 1755 phosphorylation greatly predominating in the brain. Inositol 1,4,5-trisphosphate receptor protein kinase A phosphorylation augments Ca(2+) release. To assess type 1 protein kinase A phosphorylation dynamics in the intact organism, we developed antibodies selective for either serine 1755 phosphorylated or unphosphorylated species. Immunohistochemical studies reveal marked variation in localization. For example, in the hippocampus the phosphorylated type 1 inositol 1,4,5-trisphosphate receptor is restricted to CA1, while the unphosphorylated receptor occurs ubiquitously in CA1-CA3 and dentate gyrus granule cells. Throughout the brain the phosphorylated type 1 inositol 1,4,5-trisphosphate receptor is selectively enriched in dendrites, while the unphosphorylated receptor predominates in cell bodies. Focal cerebral ischemia in rats and humans is associated with dephosphorylation of type 1 inositol 1,4,5-trisphosphate receptors, and glutamatergic excitation of cerebellar Purkinje cells mediated by ibogaine elicits dephosphorylation of type 1 inositol 1,4,5-trisphosphate receptors that precedes evidence of excitotoxic neuronal degeneration. We have demonstrated striking variations in regional and subcellular distribution of inositol 1,4,5-trisphosphate receptor phosphorylation that may influence normal physiological intracellular Ca(2+) signaling in rat and human brain. We have further shown that the subcellular distribution of inositol 1,4,5-trisphosphate receptor phosphorylation in neurons is regulated by excitatory neurotransmission, as well as excitotoxic insult and neuronal ischemia-reperfusion. Phosphorylation dynamics of type 1 inositol 1,4,5-trisphosphate receptors may modulate intracellular Ca(2+) release and influence the cellular response to neurotoxic insults.
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PMID:Differential neuronal localizations and dynamics of phosphorylated and unphosphorylated type 1 inositol 1,4,5-trisphosphate receptors. 1116 29

cAMP induces a protein-synthesis-dependent late phase of long-term potentiation (LTP) at CA3-CA1 synapses in acute hippocampal slices. Herein we report cAMP-mediated LTP and long-term depression (LTD) at monosynaptic CA3-CA1 cell pairs in organotypic hippocampal slice cultures. After bath application of the membrane-permeable cAMP analog adenosine 3',5'-cyclic monophosphorothioate, Sp isomer (Sp-cAMPS), synaptic transmission was enhanced for at least 2 h. Consistent with previous findings, the late phase of LTP requires activation of cAMP-dependent protein kinase A and protein synthesis. There is also an early phase of LTP induced by cAMP; the early phase depends on protein kinase A but, in contrast to the later phase, does not require protein synthesis. In addition, the cAMP-induced LTP is associated with a reduction of paired-pulse facilitation, suggesting that presynaptic modification may be involved. Furthermore, we found that Sp-cAMPS induced LTD in slices pretreated with picrotoxin, a gamma-aminobutyric acid type A (GABA(A)) receptor antagonist. This form of LTD depends on protein synthesis and protein phosphatase(s) and is accompanied by an increased ratio of failed synaptic transmission. These results suggest that GABA(A) receptors can modulate the effect of cAMP on synaptic transmission and thus determine the direction of synaptic plasticity.
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PMID:Gamma-aminobutyric acid type A receptors modulate cAMP-mediated long-term potentiation and long-term depression at monosynaptic CA3-CA1 synapses. 1129 64

Actions of estrogen include mechanisms leading to alterations in gene transcription that may be independent of nuclear estrogen receptors, as well as those involving direct action of the estrogen receptor on the genome. Also, the influence of estrogen in the brain appears to extend well beyond areas associated with reproduction and may include forebrain areas linked to affective and cognitive behaviors. We investigated the effects of acute and long-term estradiol benzoate (E2) treatment on total and phosphorylated cyclic AMP responsive element-binding (CREB) protein levels and on cyclic AMP response element (CRE)-DNA binding in forebrain areas of ovariectomized (OVX) rats. Long-term E2 treatment increased CRE-DNA binding in the amygdala but not in hippocampus, frontal cortex, or cerebellum. The increase in CRE-DNA binding in the amygdala was associated with increased levels of total and phosphorylated CREB (pCREB) protein during protracted E2 exposure. To localize the estrogenic effect in the amygdala and determine if an effect in one hippocampal region was masked by a lack of effect in another subregion, we performed immunolabeling of pCREB in brain structures of chronically treated OVX animals with or without E2. This treatment resulted in a significant increase in relative total immunolabeled nuclei in the anteroventral subdivision of the medial amygdala. In the hippocampus, a significant increase in relative total immunolabeled nuclei was seen in the CA1 and CA3 regions, but not in the dentate gyrus or hilus of the dentate gyrus. Acute E2 treatment resulted in increased CRE-DNA binding in the frontal cortex but not in amygdala, hippocampus, or cerebellum. However, no changes in levels of total CREB or pCREB protein were observed in the frontal cortex under E2 treatment. No changes were observed either in basal or cAMP-stimulated protein kinase A (PKA) activity or in PKA-alpha catalytic subunit immunoreactivity in the amygdala or the frontal cortex. Our study indicates that both long-term and acute treatments with estrogens influence the function of CREB in specific brain structures.
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PMID:Estrogen modulation of the cyclic AMP response element-binding protein pathway. Effects of long-term and acute treatments. 1159 79

The mossy fiber-CA3 pyramidal neuron synapse is a main component of the hippocampal trisynaptic circuitry. Recent studies, however, suggested that inhibitory interneurons are the major targets of the mossy fiber system. To study the regulation of mossy fiber-interneuron excitation, we examined unitary and compound excitatory postsynaptic currents in dentate gyrus basket cells, evoked by paired recording between granule and basket cells or extracellular stimulation of mossy fiber collaterals. The application of an associative high-frequency stimulation paradigm induced posttetanic potentiation (PTP) followed by homosynaptic long-term potentiation (LTP). Analysis of numbers of failures, coefficient of variation, and paired-pulse modulation indicated that both PTP and LTP were expressed presynaptically. The Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) did not affect PTP or LTP at a concentration of 10 mM but attenuated LTP at a concentration of 30 mM. Both forskolin, an adenylyl cyclase activator, and phorbolester diacetate, a protein kinase C stimulator, lead to a long-lasting increase in excitatory postsynaptic current amplitude. H-89, a protein kinase A inhibitor, and bisindolylmaleimide, a protein kinase C antagonist, reduced PTP, whereas only bisindolylmaleimide reduced LTP. These results may suggest a differential contribution of protein kinase A and C pathways to mossy fiber-interneuron plasticity. Interneuron PTP and LTP may provide mechanisms to maintain the balance between synaptic excitation of interneurons and that of principal neurons in the dentate gyrus-CA3 network.
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PMID:PTP and LTP at a hippocampal mossy fiber-interneuron synapse. 1173 56

Hippocampal cholinergic neurostimulating peptide (HCNP) is involved in the phenotype development of the septo-hippocampal system. HCNP precursor protein (HCNP-pp) is known to interact with other molecules including phosphatidylethanolamine and Raf-1 kinase, and is also known as phosphatidylethanolamine-binding protein and raf kinase-inhibitory protein. To assess whether HCNP-pp is involved in the pathogenesis of Alzheimer disease (AD), the expression levels of its mRNA in the hippocampus of autopsy brains from patients with dementia (including AD and ischemic vascular dementia) were compared with those of non-demented control subjects. The in situ hybridization analysis revealed that the expression of HCNP-pp mRNA in patients with clinically late-onset AD was decreased in the hippocampal CA1 field, but not in the CA3 field or the dentate gyrus. The early-onset AD patients showed a wide range of expression levels in the hippocampal sub-regions. Northern blot analysis of HCNP-pp mRNA in brain tissue supported these observations. Since HCNP is known to stimulate the enzymatic activity of choline acetyltransferase in neurons, its low expression in the CAI field of AD patients may explain the downregulation of cholinergic neurons seen in these patients and may thus contribute to the pathogenic processes underlying AD.
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PMID:Decreased expression of hippocampal cholinergic neurostimulating peptide precursor protein mRNA in the hippocampus in Alzheimer disease. 1185 19

Brain-derived neurotrophic factor (BDNF) is implicated in long-term synaptic plasticity in the adult hippocampus, but the cellular mechanisms are little understood. Here we used intrahippocampal microinfusion of BDNF to trigger long-term potentiation (BDNF-LTP) at medial perforant path--granule cell synapses in vivo. BDNF infusion led to rapid phosphorylation of the mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated protein kinase) and p38 but not JNK (c-Jun N-terminal protein kinase). These effects were restricted to the infused dentate gyrus; no changes were observed in microdissected CA3 and CA1 regions. Local infusion of MEK (MAP kinase kinase) inhibitors (PD98059 and U0126) during BDNF delivery abolished BDNF-LTP and the associated ERK activation. Application of MEK inhibitor during established BDNF-LTP had no effect. Activation of MEK-ERK is therefore required for the induction, but not the maintenance, of BDNF-LTP. BDNF-LTP was further coupled to ERK-dependent phosphorylation of the transcription factor cAMP response element-binding protein. Finally, we investigated the expression of two immediate early genes, activity-regulated cytoskeleton-associated protein (Arc) and Zif268, both of which are required for generation of late, mRNA synthesis-dependent LTP. BDNF infusion resulted in selective upregulation of mRNA and protein for Arc. In situ hybridization showed that Arc transcripts are rapidly and extensively delivered to granule cell dendrites. U0126 blocked Arc upregulation in parallel with BDNF-LTP. The results support a model in which BDNF triggers long-lasting synaptic strengthening through MEK-ERK and selective induction of the dendritic mRNA species Arc.
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PMID:Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. 1188 Apr 83

Mitogen-activated protein kinases, which play a crucial role in signal transduction, are activated by phosphorylation in response to a variety of mitogenic signals. In the present study, the authors used Western blot analysis and immunohistochemistry to show that phosphorylated extracellular signal-regulated protein kinase (p-ERK) and c-Jun NH2-terminal kinase (p-JNK), but not p38 mitogen-activated protein kinase, significantly increased in both the neurons and astrocytes after traumatic brain injury in the rat hippocampus. Different immunoreactivities of p-ERK and p-JNK were observed in the pyramidal cell layers and dentate hilar cells immediately after traumatic brain injury. Immunoreactivity for p-JNK was uniformly induced but was only transiently induced throughout all pyramidal cell layers. However, strong immunoreactivity for p-ERK was observed in the dentate hilar cells and the damaged CA3 neurons, along with the appearance of pyknotic morphologic changes. In addition, immunoreactivity for p-ERK was seen in astrocytes surrounding dentate and CA3 pyramidal neurons 6 hours after traumatic brain injury. These findings suggest that ERK and JNK but not p38 cascades may be closely involved in signal transduction in the rat hippocampus after traumatic brain injury.
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PMID:Differential activation of mitogen-activated protein kinase pathways after traumatic brain injury in the rat hippocampus. 1189 38

The possible role of protein kinase C activation in the inhibitory action of cholinergic transmitters on the slow Ca-dependent afterhyperpolarizing current (IAHP) in hippocampal CA3 pyramidal neurons was investigated using hippocampal slice cultures. IAHP was inhibited reversibly by methacholine (100 - 600 nM) and irreversibly by the protein kinase C activator, phorbol-12,13-dibutyrate (PDBu, 10 nM to 1 microM). The inhibitory action of PDBu was antagonized by prior (15 - 60 min) exposure to staurosporin (1 microM). In contrast, the inhibitory effect of methacholine on IAHP was not reduced after up to 3 h of exposure to this compound. In addition, methacholine produced a reversible inward current at the holding potential, which was augmented by staurosporin. However, prior exposure to PDBu reduced the effect of methacholine on IAHP and occluded the methacholine-induced inward current. This effect of PDBu was also observed in the presence of staurosporin, suggesting that it might be exerted through a protein kinase C-independent pathway. Noradrenalin (2 - 5 microM) and 8-bromo cyclic adenosine 3',5'monophosphate (8-Br-cAMP, 1 mM) also produced a reversible block of IAHP. Their action was antagonized by staurosporin, probably via its effect on protein kinase A. Thus the present experiments suggest that the action of muscarinic agonists on IAHP cannot be explained by an effect on protein kinase C, but support a role for protein kinase A in mediating the action of noradrenalin.
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PMID:Evidence Against a Role for Protein Kinase C in the Inhibition of the Calcium-activated Potassium Current IAHP by Muscarinic Stimulants in Rat Hippocampal Neurons. 1210 1

Stress-activated protein kinase/extracellular signal-regulated kinase-1 (SEK1/MKK4) was examined in a rat model of global brain ischemia. Western blot assay showed that SEK1 activation was biphasic in CA1 but not CA3/dentate gyrus. The second activation peak (3 days after ischemia) was prevented by pretreatment with l-naphthyl acetyl spermine (Naspm), a channel blocker of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, or N-acetylcysteine (NAC), a free radical scavenger. Concomitantly, the late activation of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal protein kinase (JNK) was also prevented by Naspm or NAC. Moreover, phospho-SEK1 and phospho-JNK co-immunoprecipitated with ASK1 and the bindings peaked at 3 days of reperfusion. Together with previous results, these findings indicate that Ca(2+)-permeable AMPA receptors are important routes to mediate the late activation of ASK1-SEK1-JNK pathway involving oxidative stress in hippocampal CA1 region after ischemia.
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PMID:Biphasic activation of apoptosis signal-regulating kinase 1-stress-activated protein kinase 1-c-Jun N-terminal protein kinase pathway is selectively mediated by Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors involving oxidative stress following brain ischemia in rat hippocampus. 1252 69


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