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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In several neurological disorders including hyperhomocysteinemia, homocysteine (Hcy) accumulates in the brain, and acts as a potent neurotoxin. However, the molecular mechanisms induced by increased levels of Hcy in brain are not well understood. Here we show an activation of the extracellular signal-regulated kinases (ERK1 and ERK2) and the downstream nuclear targets Elk-1 and calcium/cAMP response element binding protein, in the hippocampus of cystathionine beta synthase deficient mice, a murine model of hyperhomocysteinemia. An ex vivo model of hippocampal slices allowed us to reproduce Hcy -induced ERK activation and to unravel the mechanisms responsible of this activation. Of interest, N-methyl-d-aspartate (NMDA), non-NMDA and metabotropic glutamate receptor antagonists all blocked Hcy -induced ERK activation. Moreover, the ERK activation was blocked in the presence of Na+-channel blocker tetrodotoxin, indicating the existence of a trans-synaptic activity in ERK activation by Hcy in hippocampal slices. The effects of Hcy on ERK cascade activation were also dependent on calcium influx, CaMK-II, PKC as well as PKA activation. Thus, altogether these data support a role of Hcy on ERK activation, via complex mechanisms, starting with a control of glutamate release, which in turn activates ionotropic and metabotropic receptor subtypes and produces increases in intracellular calcium levels.
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PMID:Regulation of extracellular signal-regulated kinase by homocysteine in hippocampus. 1591 60

Gliosis is a hypertrophic and hyperplastic response to many types of central nervous system injury, including trauma, stroke, seizure, as well as neurodegenerative and demyelinating disorders. Reactive astrocytes, a major component of the glial scar, express molecules that can both inhibit and promote axonal regeneration. ATP, which is released upon traumatic injury, hypoxia, and cell death, contributes to the gliotic response by binding to specific cell surface astrocytic P2 nucleotide receptors and evoking characteristic features of gliosis such as increased expression of glial fibrillary acidic protein (GFAP), generation and elongation of astrocytic processes, and cellular proliferation. Here, we review recent studies that demonstrate that (1) metabotropic, P2Y, and ionotropic, P2X, receptors expressed in astrocytes are coupled to protein kinase signaling pathways that regulate cellular proliferation, differentiation, and survival such as ERK and protein kinase B/Akt and (2) these P2 receptor/protein kinase cascades are activated after trauma induced by mechanical strain. We suggest that P2 receptor/protein kinase signaling pathways might provide novel therapeutic targets to regulate the formation of reactive astrocytes and the production of molecules that affect axonal regeneration and neurodegeneration.
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PMID:Signaling from P2 nucleotide receptors to protein kinase cascades induced by CNS injury: implications for reactive gliosis and neurodegeneration. 1595 14

Dinucleoside polyphosphates or Ap(n)A are a family of dinucleotides formed by two adenosines joined by a variable number of phosphates. Ap(4)A, Ap(5)A, and Ap(6)A are stored together with other neurotransmitters into secretory vesicles and are co-released to the extracellular medium upon stimulation. These compounds can interact extracellularly with some ATP receptors, both metabotropic (P2Y) and ionotropic (P2X). However, specific receptors for these substances, other than ATP receptors, have been described in presynaptic terminals form rat midbrain. These specific dinucleotide receptors are of ionotropic nature and their activation induces calcium entry into the terminals and the subsequent neurotransmitter release. Calcium signals that cannot be attributable to the interaction of Ap(n)A with ATP receptors have also been described in cerebellar synaptosomes and granule cell neurons in culture, where Ap(5)A induces CaMKII activation. In addition, cerebellar astrocytes express a specific Ap(5)A receptor coupled to ERK activation. Ap(5)A engaged to MAPK cascade by a mechanism that was insensitive to pertussis toxin and required the involvement of src and ras proteins. Diadenosine polyphosphates, acting on their specific receptors and/or ATP receptors, can also interact with other neurotransmitter systems. This broad range of actions and interactions open a promising perspective for some relevant physiological roles for the dinucleotides. However, the physiological significance of these compounds in the CNS is still to be determined.
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PMID:Dinucleoside polyphosphates and their interaction with other nucleotide signaling pathways. 1668 66

Glycogen synthase kinase (GSK)-3 was identified initially as an enzyme that regulates glycogen synthesis in response to insulin, but more recent studies indicate that it is also involved in numerous cellular processes, including cell survival, cell cycle regulation, proliferation, and differentiation. Because extracellular ATP exerts trophic actions on astrocytes, we investigated a possible signaling linkage from P2 purinergic receptors to GSK3beta. Addition of ATP to primary cultures of rat cortical astrocytes resulted in phosphorylation of Ser9 on GSK3beta and a concomitant decrease in GSK3 activity. UTP and 2',3'-O-(4-benzoyl)-benzoyl ATP (BzATP) increased phosphorylation of Ser9 on GSK3beta indicating that metabotropic P2Y and ionotropic P2X receptors are coupled to GSK3beta. Signaling studies showed that phosphorylation of Ser9-GSK3beta in response to ATP was inhibited by downregulation of protein kinase C (PKC) but not by blockade of Akt or p70 S6 kinase pathways. PKC also links P2 receptors to ERK in astrocytes, but inhibition of ERK signaling did not block phosphorylation of Ser9-GSK3beta stimulated by P2 receptors. Mechanical strain, which releases ATP, also stimulated Ser9 phosphorylation and this was attenuated by hydrolysis of extracellular ATP with apyrase or by blockade of P2 receptors. We conclude that P2 receptors are coupled to GSK3beta by a PKC-dependent pathway that is independent of Akt, p70 S6 kinase, and ERK pathways. These findings suggest that purinergic signaling contributes to the regulation of GSK3beta functions, one of which may be the response of astrocytes to CNS injury on release of ATP.
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PMID:P2 purinergic receptors signal to glycogen synthase kinase-3beta in astrocytes. 1681 Jun 87

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABA(A)/GABA(C)) and metabotropic (GABA(B)) receptors (R). In addition to their location on neurons, GABA and functional GABA(B) receptors have been detected in nonneuronal cells in peripheral tissue. Although the GABA(B)R has been shown to function as a prejunctional inhibitory receptor on parasympathetic nerves in the lung, the expression and functional coupling of GABA(B) receptors to G(i) in airway smooth muscle itself have never been described. We detected the mRNA encoding multiple-splice variants of the GABA(B)R1 and GABA(B)R2 in total RNA isolated from native human and guinea pig airway smooth muscle and from RNA isolated from cultured human airway smooth muscle (HASM) cells. Immunoblots identified the GABA(B)R1 and GABA(B)R2 proteins in human native and cultured airway smooth muscle. The GABA(B)R1 protein was immunohistochemically localized to airway smooth muscle in guinea pig tracheal rings. Baclofen, a GABA(B)R agonist, elicited a concentration-dependent stimulation of [(35)S]GTPgammaS binding in HASM homogenates that was abrogated by the GABA(B)R antagonist CGP-35348. Baclofen also inhibited adenylyl cyclase activity and induced ERK phosphorylation in HASM. Another GABA(B)R agonist, SKF-97541, mimicked while pertussis toxin blocked baclofen's effect on ERK phosphorylation, implicating G(i) protein coupling. Functional GABA(B) receptors are expressed in HASM. GABA may modulate an uncharacterized signaling cascade via GABA(B) receptors coupled to the G(i) protein in airway smooth muscle.
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PMID:Functional expression of the GABAB receptor in human airway smooth muscle. 1682 28

Toll-like receptor 3 (TLR3) is a component of the innate immune response that responds to dsRNA viruses and virus replication intermediates. In this study we show that activation of astrocytes with the dsRNA mimetic polyinosinic-cytidylic acid (pI:C) results in loss of expression of connexin43 (Cx43) mRNA and protein while upregulating the expression of the ionotropic P2 receptor P2X(4)R. Analysis of the signaling pathways involved failed to demonstrate a role for the p38 MAP kinase, ERK, or JNK signaling pathways whereas an inhibitor of the PI3 kinase/Akt pathway effectively blocked the action of pI:C. Using adenoviral vectors containing a super-repressor of NF-kappaB (NF-kappaB SR) construct or a dominant negative interferon regulatory factor 3 (dnIRF3) construct showed that inhibition of both transcription factors also blocked the effects of pI:C. To explore the functional consequences of pI:C activation we used a pore-forming assay for P2X(4)R activity and a scrape loading assay for gap junction intercellular communication (GJIC). No pore-forming activity consistent with functional P2X(4)R expression was detected in either control or activated astrocytes. In contrast, robust Lucifer yellow transfer indicative of GJIC was detected in resting cells that was lost following pI:C activation. The dnIRF3 construct failed to restore GJIC whereas the NF-kappaB SR or the NF-kappaB inhibitor BAY11-7082 and the PI3K inhibitor LY294002 all significantly reversed the effect of pI:C on GJ connectivity. We conclude that activation of the innate immune response in astrocytes is associated with functional loss of GJIC through a pathway involving NF-kappaB and PI3 kinase.
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PMID:The TLR3 ligand polyI: C downregulates connexin 43 expression and function in astrocytes by a mechanism involving the NF-kappaB and PI3 kinase pathways. 1695 87

Glutamate receptors regulate gene expression in neurons by activating intracellular signaling cascades that phosphorylate transcription factors within the nucleus. The mitogen-activated protein kinase (MAPK) cascade is one of the best characterized cascades in this regulatory process. The Ca(2+)-permeable ionotropic glutamate receptor, mainly the NMDA receptor subtype, activates MAPKs through a biochemical route involving the Ca(2+)-sensitive Ras-guanine nucleotide releasing factor, Ca(2+)/calmodulin-dependent protein kinase II, and phosphoinositide 3-kinase. The metabotropic glutamate receptor (mGluR), however, activates MAPKs primarily through a Ca(2+)-insensitve pathway involving the transactivation of receptor tyrosine kinases. The adaptor protein Homer also plays a role in this process. As an information superhighway between surface glutamate receptors and transcription factors in the nucleus, active MAPKs phosphorylate specific transcription factors (Elk-1 and CREB), and thereby regulate distinct programs of gene expression. The regulated gene expression contributes to the development of multiple forms of synaptic plasticity related to long-lasting changes in memory function and addictive properties of drugs of abuse. This review, by focusing on new data from recent years, discusses the signaling mechanisms by which different types of glutamate receptors activate MAPKs, features of each MAPK cascade in regulating gene expression, and the importance of glutamate/MAPK-dependent synaptic plasticity in memory and addiction.
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PMID:Regulation of mitogen-activated protein kinases by glutamate receptors. 1701 22

The P2X(7) receptor is an ATP-gated ionotropic receptor that is permeable for small cations including Ca(2+) ions. Using 293 cells expressing P2X(7) receptors, we show that the P2X(7) receptor-specific ligand 2',3'-O-(4-benzoyl-benzoyl)-ATP (BzATP) induces a signaling cascade leading to the biosynthesis of biologically active Egr-1, a zinc finger transcription factor. BzATP-triggered Egr-1 biosynthesis was attenuated by the mitogen-activated protein kinase kinase inhibitor PD98059, by BAPTA-AM, the acetoxymethylester of the cytosolic Ca(2+) chelator BAPTA, and by an epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor (AG1478). These results indicate that phosphorylation and activation of extracellular signal-regulated protein kinase ERK, elevated levels of intracellular Ca(2+) and the transactivation of the EGF receptor are essential for BzATP-induced upregulation of Egr-1. The requirement of Ca(2+) within the signaling cascade was upstream of Raf kinase activation. Lentiviral-mediated expression of MAP kinase phosphatase-1 (MKP-1), a dual-specific phosphatase that dephosphorylates and inactivates ERK in the nucleus, inhibited Egr-1 biosynthesis following BzATP stimulation, indicating that MKP-1 functions as a nuclear shut-off device. Furthermore, the ternary complex factor Elk-1 was phosphorylated and the transcriptional activation potential of Elk-1 was enhanced following P2X(7) receptor stimulation. Expression of a dominant-negative mutant of Elk-1 impaired BzATP-induced upregulation of Egr-1 biosynthesis. Thus, Elk-1 connects the intracellular signaling cascade elicited by activation of P2X(7) receptors with the transcription of the Egr-1 gene.
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PMID:P2X(7) receptor stimulation upregulates Egr-1 biosynthesis involving a cytosolic Ca(2+) rise, transactivation of the EGF receptor and phosphorylation of ERK and Elk-1. 1747 86

Specification of neurotransmitter phenotype is critical for neural circuit development and is influenced by intrinsic and extrinsic factors. Recent findings in rat hypothalamus in vitro suggest the role of neurotransmitter glutamate in the regulation of cholinergic phenotype. Here we extended our previous studies on the mechanisms of glutamate-dependent regulation of cholinergic phenotypic properties in hypothalamic neurons. Using immunocytochemistry, electrophysiology, and calcium imaging, we demonstrate that hypothalamic expression of choline acetyltransferase (the cholinergic marker) and responsiveness of neurons to acetylcholine (ACh) receptor agonists increase during chronic administration of an N-methyl-D-aspartate receptor (NMDAR) blocker, MK-801, in developing rats in vivo and genetic and pharmacological inactivation of NMDARs in mouse and rat developing neuronal cultures. In hypothalamic cultures, an inactivation of NMDA receptors also induces ACh-dependent synaptic activity, as do inactivations of PKA, ERK/MAPK, CREB, and NF-kappaB, which are known to be regulated by NMDA receptors. Interestingly, the increase in cholinergic properties in developing neurons that is induced by NMDAR blockade is prevented by the blockade of ACh receptors, suggesting that function of ACh receptor is required for the cholinergic up-regulation. Using dual recording of monosynaptic excitatory postsynaptic currents, we further demonstrate that chronic inactivation of ionotropic glutamate receptors induces the cholinergic phenotype in a subset of glutamatergic neurons. The phenotypic switch is partial as ACh and glutamate are coreleased. The results suggest that developing neurons may not only coexpress multiple transmitter phenotypes, but can also change the phenotypes following changes in signaling in neuronal circuits.
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PMID:Regulation of cholinergic phenotype in developing neurons. 1832 6

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABA(A)) and metabotropic (GABA(B)) receptors. The GABA(B) receptor is a dimer composed of R1 and R2 components and classically couples to the heterotrimeric G(i) protein. In addition to their location on neurons, GABA and functional GABA(B) receptors have been detected in peripheral tissue such as airway smooth muscle. We questioned whether airway epithelium expresses receptors that could respond to GABA. We detected the mRNA encoding multiple-splice variants of the GABA(B)R1 and GABA(B)R2 in total RNA isolated from native human and guinea pig airway epithelium and human airway epithelial cell lines (BEAS-2B and H441). Immunoblots identified the GABA(B)R1 and GABA(B)R2 proteins in both guinea pig airway epithelium and BEAS-2B cells. The expression of GABA(B)R1 protein was immunohistochemically localized to basal mucin-secreting and ciliated columnar epithelial cells in guinea pig trachea. Baclofen inhibited adenylyl cyclase activity, induced ERK phosphorylation and cross-regulated phospholipase C, leading to increased inositol phosphates in BEAS-2B cells in a pertussis toxin-sensitive manner, implicating G(i) protein coupling. Thus, these receptors couple to G(i) and cross-regulate the phospholipase C/inositol phosphate pathway. The second messengers of these pathways, cyclic AMP and calcium, play pivotal roles in airway epithelial cell primary functions of mucus clearance. Furthermore, the enzyme that synthesizes GABA, glutamic acid decarboxylase (GAD65/67), was also localized to airway epithelium. GABA may modulate an uncharacterized signaling cascade via GABA(B) receptors coupled to G(i) protein in airway epithelium.
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PMID:Functional expression of GABAB receptors in airway epithelium. 1840 80


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