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)

Estrogen rapidly alters the excitability of hypothalamic neurons that are involved in regulating numerous homeostatic functions including reproduction, stress responses, feeding, and motivated behaviors. Neurosecretory neurons, such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons, such as pro-opiomelanocortin (POMC) and gamma-aminobutyric acid (GABA) neurons, are among those involved. We have identified membrane-initiated, rapid-signaling pathways through which 17beta-estradiol (E(2)) alters synaptic responses in these neurons using whole-cell patch recording in hypothalamic slices from ovariectomized female guinea pigs. E(2) rapidly uncouples micro -opioid and GABA(B) receptors from G-protein-gated inwardly rectifying K(+) (GIRK) channels in POMC and dopamine neurons as manifested by a reduction in the potency of micro -opioid and GABA(B) receptor agonists to activate these channels. These effects are mimicked by the selective E(2) receptor modulators raloxifene and 4OH-tamoxifen, the membrane impermeable E(2)-bovine serum albumin (BSA), but not by 17alpha-estradiol. Furthermore, the anti-estrogen ICI 182,780 antagonizes these rapid effects of E(2). Inhibitors of phospholipase C, protein kinase C, and protein kinase A block the actions of E(2), indicating that the E(2) receptor is G-protein-coupled to activation of this cascade. Conversely, estrogen enhances the efficacy of alpha1-adrenergic receptor agonists to inhibit apamin-sensitive small-conductance, Ca(2+)-activated K(+) (SK) currents in preoptic GABAergic neurons; it does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate that E(2) can modulate K(+) channels in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions through multiple intracellular signaling pathways.
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PMID:Estrogen modulation of G-protein-coupled receptor activation of potassium channels in the central nervous system. 1499 35

Several lines of evidence indicate that gamma-aminobutyric acid (GABA) type A (GABA(A)) receptors regulate memory consolidation. Here we studied the effect on consolidation of the selective antagonist of GABA(A) receptors, bicuculline, given into several regions of the cortex at different times after one-trial step-down inhibitory avoidance (0.5 mA, 2-s footshock). Rats were bilaterally implanted with cannulae aimed at the CA1 region of the dorsal hippocampus, entorhinal cortex or posterior parietal cortex, three areas known to be involved in the memory consolidation of this task. At different times after training, bicuculline (0.5 microg/side) was infused into the above mentioned structures. Bicuculline increased memory retention when administered either immediately or 1.5h after training into CA1, and both immediately and 3h after training in the entorhinal or parietal cortex. Thus, in agreement with previous findings using other drugs, the response was biphasic in these latter structures. This suggests that GABAergic mechanisms normally downregulate, memory processing by inhibiting on-going activities necessary for consolidation at the times in which bicuculline was effective in each structure. Based on previous findings, in the hippocampus, such activity involves a number of receptors and signaling pathways in the first 1.5h after training. In the entorhinal and parietal cortex memory-related activities include the participation of protein kinase A and extracellularly regulated kinase (ERK) twice, right after training and then again 3h later.
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PMID:Different time course for the memory facilitating effect of bicuculline in hippocampus, entorhinal cortex, and posterior parietal cortex of rats. 1518 70

Fibroblast growth factor (FGF)-1 is increased in particular brain regions after birth, suggesting an involvement of some regulatory neuronal circuits. To address the neuronal activity responsible for FGF-1 synthesis, effects of various neurotransmitter receptor activation on cellular FGF-1 content were examined using cultured rat cortical neurons. Histamine, glutamate, carbachol, serotonin or gamma-aminobutyric acid (GABA) caused an increase of FGF-1 content. Because this effect was mimicked by (1) N-methyl-D-aspartate, a glutamatergic agonist; (2) Ca(2+) ionophore; (3) depolarization with high concentration of KCl, but was abolished in Ca(2+)-free medium, Ca(2+) influx was thought to trigger FGF-1 synthesis. Such Ca(2+)-mediated enhancement of FGF-1 synthesis, however, did not occur in the presence of norepinephrine (NE), but was restored by KT-5720, an inhibitor of protein kinase A (PKA), suggesting an interplay between Ca(2+)-activated and cAMP/PKA signals for neuronal FGF-1 synthesis. This mechanism was proved to function in vivo by stimulation of FGF-1 expression in neurons of the cerebral cortex after intracerebral administration of propranolol, an antagonist of adrenergic beta receptors. This demonstrates that FGF-1 synthesis is essentially upregulated by Ca(2+) influx through excitatory neuronal activities, but such an effect is abolished by neurotransmission that evokes cAMP/PKA signals. FGF-1 produced is thought to act on establishment and maintenance of particular neuronal circuits in the brain, which may be one of the ways neurotransmitters regulate brain function.
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PMID:Cyclic AMP/protein kinase a signal attenuates Ca(2+)-induced fibroblast growth factor-1 synthesis in rat cortical neurons. 1526 18

The GABAA receptor beta subunit is required to confer sensitivity to gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. In previous studies we demonstrated that the growth and differentiation factor neuregulin 1 (NRG1) selectively induced expression of the beta2 subunit mRNA and encoded protein in rat cerebellar granule neurons in culture. In the present report we examine the signaling pathways that mediate this effect. These studies demonstrate that the effects of NRG1 on beta2 subunit polypeptide expression require activation of the ErbB4 receptor tyrosine kinase; its effects are inhibited by pharmacological blockade of ErbB4 phosphorylation or reduction of receptor level with an antisense oligodeoxynucleotide. The NRG1-induced activation of ErbB4 stimulates the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and cyclin-dependent kinase-5 (cdk5) pathways. Pharmacological blockade of any of these pathways inhibits increased beta2 subunit expression, demonstrating that all three pathways are required to mediate the effects of NRG1 on GABAA receptor subunit expression in cerebellar granule neurons. These studies provide novel information concerning the actions of NRG1 on GABAA receptor expression in the CNS.
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PMID:Neuregulin induces GABAA receptor beta2 subunit expression in cultured rat cerebellar granule neurons by activating multiple signaling pathways. 1534 35

Hyponatremia leads to hyperexcitability of neurons, seizures, and coma. It is well established that uptake of neurotransmitters is a sodium-dependent process. Therefore, we suggest that inhibition of neurotransmitter uptake can lead to the clinical manifestations of hyponatremia. Decreasing of sodium concentration down to 92 mM in incubation medium, which corresponds to lowering the osmolarity down to 230 mOsm/l, leads to a 45% decrease in glutamate uptake and a 46% decrease in gamma-aminobutyric acid (GABA) uptake. However, this effect was mediated by the nonspecific lowering of osmolarity rather than by decreasing sodium concentration. Hypotonic shock was able to reduce glutamate uptake in the presence of protein kinase inhibitors staurosporine and genistein, the phosphatase inhibitor okadaic acid, the phosphatidylinositol 3-kinase inhibitor wortmannin, and cytoskeleton modulators colchicine and cytochalasin B. Therefore, we suggest that intracellular signaling is not mediating the effect of osmolarity reduction on neurotransmitter uptake.
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PMID:Influence of hypotonic shock on glutamate and GABA uptake in rat brain synaptosomes. 1545 59

We recently reported that cholecystokinin (CCK) excited nucleus accumbens (NAc) cells and depressed excitatory synaptic transmission indirectly through gamma-aminobutyric acid (GABA), acting on presynaptic GABAB receptors (Kombian et al. [2004] J. Physiol. 555:71-84). The present study tested the hypothesis that CCK modulates inhibitory synaptic transmission in the NAc. Using in vitro forebrain slices containing the NAc and whole-cell patch recording, we examined the effects of CCK on evoked inhibitory postsynaptic currents (IPSCs) recorded at a holding potential of -80 mV throughout CCK-8S caused a reversible inward current accompanied by a concentration-dependent decrease in evoked IPSC amplitude. Maximum IPSC depression was approximately 25% at 10 microM, with an estimated EC50 of 0.1 microM. At 1 microM, CCK-8S induced an inward current of 28.3 +/- 4.8 pA (n=6) accompanied by an IPSC depression of -18.8% +/- 1.6% (n=6). This CCK-induced IPSC depression was blocked by pretreatment with proglumide (100 microM; -3.7% +/- 6.9%; n=4) and by LY225910 (100 nM), a selective CCKB receptor antagonist (4.4% +/- 2.6%; n=4). It was not blocked by SCH23390 (10 microM; -23.5% +/- 1.3%; P < 0.05; n=7) or sulpiride (10 microM; -21.8% +/- 5.1%; P <0.05; n=4), dopamine receptor antagonists. By contrast, it was blocked by CGP55845 (1 microM; -0.4% +/- 3.4%; n=5) a potent GABAB receptor antagonist, and by forskolin (50 microM; 9.9% +/- 5.2%; n=4), an adenylyl cyclase activator, and H-89 (1 microM; 6.9% +/- 3.9%; n=4), a protein kinase A (PKA) inhibitor. These results indicate that CCK acts on CCKB receptors to increase extracellular levels of GABA, which then acts on GABAB receptors to decrease IPSC amplitude.
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PMID:Cholecystokinin inhibits evoked inhibitory postsynaptic currents in the rat nucleus accumbens indirectly through gamma-aminobutyric acid and gamma-aminobutyric acid type B receptors. 1560 83

Hypothalamic target neurons of estrogen include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and gamma-aminobutyric acid (GABA) neurons. These and other hypothalamic neurons are involved in regulating numerous homeostatic functions including reproduction, thermoregulation, stress responses, feeding and motivated behaviors. Using a combination of techniques to examine the molecular mechanisms leading to physiological changes induced by estrogen, we find that both rapid effects and transcriptional changes alter excitability of hypothalamic neurons. We have identified membrane-initiated, rapid signaling pathways through which 17beta-estradiol (E2) alters synaptic responses in these neurons using whole-cell patch recording in hypothalamic slices from ovariectomized female guinea pigs. E2 rapidly uncouples mu-opioid and GABA(B) receptors from G protein-gated inwardly rectifying K+ (GIRK) channels in POMC and dopamine neurons as manifested by a reduction in the potency of mu-opioid and GABA(B) receptor agonists to activate these channels. Inhibitors of phospholipase C, protein kinase C and protein kinase A block the actions of E2, indicative that the E2 receptor is G protein-coupled to activation of this cascade. Taking advantage of an animal model we developed to investigate estrogen's feedback actions on secretion of gonadotropin-releasing hormone (GnRH), we studied the transcriptional changes induced by estrogen using suppression subtractive hybridization (SSH) and microarray analysis. Many of the observed mRNA expression changes include transcripts encoding proteins critical for neurotransmitter release and receptor dynamics. Some of these include gec-1, PI3-kinase p55gamma, rab11a GTPase, synaptobrevin2, synaptogyrin, taxilin, Ca2+-dependent activator protein for secretion (CAPS) and a number of proteins containing pleckstrin homology domains-domains that are involved in plasma membrane targeting of their host protein. In situ hybridization and quantitative film autoradiography analysis on selected transcripts show differential distribution and expression in hypothalamic nuclei. Furthermore, single-cell PCR analysis reveals these genes to be expressed in neurons such as POMC (and GnRH). Whether these expression changes are mediated by the classical or membrane estrogen receptors has yet to be delineated. More detailed investigations of transcript spatial localization within neurons and their temporal expression, i.e., within minutes or hours, will provide more insight regarding how estrogen alters neuronal excitability and synaptic efficacy that ultimately lead to changes in complex behavior.
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PMID:Estrogen modulation of hypothalamic neurons: activation of multiple signaling pathways and gene expression changes. 1586 23

Alterations in synaptic transmission within the spinal cord dorsal horn play a key role in the development of pathological pain. While N-methyl-D-aspartate (NMDA) receptors and activity-dependent synaptic plasticity have been the focus of research for many years, recent evidence attributes very specific functions to inhibitory glycinergic and gamma-aminobutyric acid (GABA)-ergic neurotransmission in the generation of inflammatory and neuropathic pain. The central component of inflammatory pain originates from a disinhibition of dorsal horn neurons, which are relieved from glycinergic neurotransmission by the inflammatory mediator prostaglandin E2 (PGE2). PGE2 activates prostaglandin E receptors of the EP2 subtype and leads to a protein kinase A-dependent phosphorylation and inhibition of glycine receptors containing the alpha3 subunit (GlyRalpha3). This GlyRalpha3 is distinctly expressed in the superficial dorsal horn, where nociceptive afferents terminate. Other but probably very similar disinhibitory mechanisms may well contribute to abnormal pain occurring after peripheral nerve injury.
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PMID:The glycinergic control of spinal pain processing. 1596 63

Topiramate (TPM) is a structurally novel broad spectrum anticonvulsant known to have a negative modulatory effect on the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate subtypes of glutamate receptors and some types of voltage-gated Na(+) and Ca(2+) channels, and a positive modulatory effect on some types of gamma-aminobutyric acid(A) (GABA(A)) receptors and at least one type of K(+) channels in neurons. In an earlier work, we showed that the negative modulatory effect of TPM (100 mum) on AMPA/kainate receptors in neurons is dependent on TPM modulation of the phosphorylation state of these receptors. In this work, we investigated the effect of TPM on AMPA-induced intracellular calcium ([Ca(2+)](i)) responses in cultured rat cortical astrocytes, with special interest in intracellular mechanisms. Here, we report that the ability of TPM (1-100 mum) to inhibit AMPA-induced accumulation of Ca(2+) in astrocytes is inversely related to the level of protein kinase A (PKA) -mediated phosphorylation of channels activated by AMPA. The level of receptor phosphorylation was further determined with western blot using phosphorylation specific antibodies that recognize the glutamate receptor 1 (GluR1) subunit phosphorylated on Ser845. These results demonstrated that, even in cultured cortical astrocytes, TPM significantly reduced the phophorylation level of GluR1 subunits. Furthermore, it was shown that TPM binds to AMPA receptors in the dephosphorylated state and thereby exerts an allosteric modulatory effect on the ion channel.
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PMID:Topiramate reduces AMPA-induced Ca(2+) transients and inhibits GluR1 subunit phosphorylation in astrocytes from primary cultures. 1609 49

Gamma-aminobutyric acid (GABA), which is inhibitory in the adult central nervous system, can be excitatory in the developing brain. The change from excitatory to inhibitory action of GABA during development is caused by a negative shift in its reversal potential. Here, we report a presynaptic activity-mediated negative shift in the reversal potential of the GABA-mediated synaptic currents in immature deep cerebellar nuclei neurons. This shift appears to be due to an increased expression and activation of the K+-Cl- co-transporter type 2 (KCC-2) through the activation of protein kinase A, protein synthesis and activation of protein phosphatases. Thus, maturation of the GABA response may rely on an activity-dependent up-regulation of KCC-2.
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PMID:Activity-mediated shift in reversal potential of GABA-ergic synaptic currents in immature neurons. 1620 42


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