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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate receptor activation of mitogen-activated protein (MAP) kinase signalling cascades has been implicated in diverse neuronal functions such as synaptic plasticity, development and excitotoxicity. We have previously shown that Ca2+-influx through NMDA receptors in cultured striatal neurones mediates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt/protein kinase B (PKB) through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. Exposing neurones to the Src family tyrosine kinase inhibitor PP2, but not the inactive analogue PP3, inhibited NMDA receptor-induced phosphorylation of ERK1/2 and Akt/PKB in a concentration-dependent manner, and reduced cAMP response element-binding protein (CREB) phosphorylation. To establish a link between Src family tyrosine kinase-mediated phosphorylation and PI 3-kinase signalling, affinity precipitation experiments were performed with the SH2 domains of the PI 3-kinase regulatory subunit p85. This revealed a Src-dependent phosphorylation of a focal adhesion kinase (FAK)-p85 complex on glutamate stimulation. Demonstrating that PI3-kinase is not ubiquitously involved in NMDA receptor signal transduction, the PI 3-kinase inhibitors wortmannin and LY294002 did not prevent NMDA receptor Ca2+-dependent phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2). Further, inhibiting Src family kinases increased NMDA receptor-dependent JNK1/2 phosphorylation, suggesting that Src family kinase-dependent cascades may physiologically limit signalling to JNK. These results demonstrate that Src family tyrosine kinases and PI3-kinase are pivotal regulators of NMDA receptor signalling to ERK/Akt and JNK in striatal neurones.
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PMID:Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones. 1500 68

Gamma-aminobutyric acid B (GABAB) receptors (GBRs) are G-protein-coupled receptors that mediate a slow, prolonged form of inhibition in the basolateral amygdala (ABL) and other brain areas. Recent studies indicate that this receptor is a heterodimer consisting of GABABR1 (GBR1) and GABABR2 subunits. In the present investigation, antibodies to the GABABR1 subunit were used to study the neuronal localization of GBRs in the rat ABL. GBR immunoreactivity was mainly found in spine-sparse interneurons and astrocytes at the light microscopic level. Very few pyramidal neurons exhibited perikaryal staining. Dual-labeling immunofluorescence analysis indicated that each of the four main subpopulations of interneurons exhibited GBR immunoreactivity. Virtually 100% of large CCK+ neurons in the basolateral and lateral nuclei were GBR+. In the basolateral nucleus 72% of somatostatin (SOM), 73% of parvalbumin (PV) and 25% of VIP positive interneurons were GBR+. In the lateral nucleus 50% of somatostatin, 30% of parvalbumin and 27% of VIP positive interneurons were GBR+. Electron microscopic (EM) analysis revealed that most of the light neuropil staining seen at the light microscopic level was due to the staining of dendritic shafts and spines, most of which probably belonged to spiny pyramidal cells. Very few axon terminals (Ats) were GBR+. In summary, this investigation demonstrates that the distal dendrites of pyramidal cells, and varying percentages of each of the four main subpopulations of interneurons in the ABL, express GBRs. Because previous studies suggest that GBR-mediated inhibition modulates NMDA-dependent EPSPs in the ABL, these receptors may play an important role in neuronal plasticity related to emotional learning.
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PMID:Immunocytochemical localization of GABABR1 receptor subunits in the basolateral amygdala. 1527 73

Mechanical forces influence articular cartilage structure by regulating chondrocyte activity. Mechanical stimulation results in activation of an alpha5beta1 integrin dependent intracellular signal cascade involving focal adhesion kinase and protein kinase C, triggering the release of interleukin-4 from the cell. In normal HAC the response to physiological mechanical stimulation is characterised by increased levels of aggrecan mRNA and a decrease in levels of mRNA for matrix metalloproteinase 3 (MMP-3), the net result of which would be to maintain and optimise cartilage structure and function. This protective/anabolic response is not seen when chondrocytes from osteoarthritic cartilage are subjected to an identical mechanical stimulation regime. Following the observation that the neurotransmitter substance P is involved in chondrocyte mechanotransduction the present study was undertaken to establish potential roles for glutamate receptors in the control of chondrocyte mechanical responses. Using immunohistochemistry and RTPCR normal and OA chondrocytes are shown to express NR1 and NR2a subunits of the NMDA receptor. Addition of NMDA receptor agonists to chondrocytes in primary culture resulted in changes in membrane potential consistent with expression of functional receptors. NMDA receptor antagonists inhibited the hyperpolarisation response of normal chondrocytes to mechanical stimulation but had no effect on the depolarisation response of osteoarthritic chondrocytes to mechanical stimulation. These studies indicate that at least one subset of the NMDA receptor family of molecules is expressed in cartilage and may have important modulatory effects on mechanotransduction and cellular responses following mechanical stimulation. Indeed the results suggest that there is an alteration of NMDA receptor signalling in OA chondrocytes, which may be critical in the abnormal response of OA chondrocytes to mechanical stimulation. Thus NMDA receptors appear to be involved in the regulation of human articular chondrocyte responses to mechanical stimulation, and in OA, mechanotransduction pathways may be modified as a result of altered activation and function of these receptors.
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PMID:NMDA receptor expression and roles in human articular chondrocyte mechanotransduction. 1529 60

The present study evaluated the role of nitric oxide (NO) in the transfer latency (TL) paradigm in the elevated plus-maze. Male Wistar rats received i.p. injections of either 0.9% Saline, N(omega) Nitro-L-arginine-methyl-ester (L-NAME, an inhibitor of NO synthesis), d-NAME (inert isomer), scopolamine (SCO, antagonist of muscarinic receptors), or MK-801 (antagonist of NMDA receptors) and, after 30 min, were submitted to TL procedure. In an independent experiment, the ability of the same L-NAME treatments in changing the arterial pressure and blood glucose level (BGL) was evaluated in conscious rats. The treatment with SCO (1 mg kg(-1)), MK-801 (0.15 mg kg(-1)) and L-NAME (10 and 50 mg kg(-1)), but not with D-NAME, impaired the TL learning. The L-NAME-induced TL deficit was counteracted by L-ARG (100 and 200 mg kg(-1)), while the co-administration of sub-effective doses of L-NAME and MK-801 failed to impair the TL learning. The L-NAME (50 mg kg(-1)) treatment failed to alter the BGL. All treatments with L-NAME induced hypertension, but the rats treated with L-NAME (5 mg kg(-1)) were still able to learn the TL task. The data indicate that the TL deficit induced by L-NAME (10 and 50 mg kg(-1)) is not due to either hypertension or changes in the BGL. It is also possible to establish that NO production is important for emotional learning underlying the TL procedure in rats.
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PMID:The role of nitric oxide in the emotional learning of rats in the plus-maze. 1576 71

Integrin class adhesion proteins are concentrated at adult brain synapses. Whether synaptic integrins engage kinase signaling cascades has not been determined, but is a question of importance to ideas about integrin involvement in functional synaptic plasticity. Accordingly, synaptoneurosomes from adult rat brain were used to test if matrix ligands activate integrin-associated tyrosine kinases, and if integrin signaling targets include NMDA-class glutamate neurotransmitter receptors. The integrin ligand peptide Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) induced rapid (within 5 min) and robust increases in tyrosine phosphorylation of focal adhesion kinase, proline-rich tyrosine kinase 2 and Src family kinases. Increases were similarly induced by the native ligand fibronectin, blocked with neutralizing antibodies to beta1 integrin, and not obtained with control peptides, indicating that kinase activation was integrin-mediated. Both GRGDSP and fibronectin caused rapid Src kinase-dependent increases in tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B in synaptoneurosomes and acute hippocampal slices. Tests of the physiological significance of the latter result showed that ligand treatment caused a rapid and beta1 integrin-dependent increase in NMDA receptor-mediated synaptic responses. These results provide the first evidence that, in adult brain, synaptic integrins activate local kinase cascades with potent effects on the operation of nearby neurotransmitter receptors implicated in synaptic plasticity.
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PMID:Integrin signaling cascades are operational in adult hippocampal synapses and modulate NMDA receptor physiology. 1585 87

The hippocampus produces growth hormone (GH) and contains GH receptors, suggesting a potential role for GH signaling in the regulation of hippocampal function. In agreement with this possibility, previous investigations have found altered hippocampal function and hippocampal-dependent learning and memory after chronic GH administration or deficiency. In this study we applied GH to in vitro rat hippocampal brain slices, to determine whether GH has short-term effects on hippocampal function in addition to previously documented chronic effects. We found that GH enhanced both AMPA- and NMDA-receptor-mediated excitatory postsynaptic potentials (EPSPs) in hippocampal area CA1, but did not alter GABA(A)-receptor-mediated inhibitory synaptic transmission. GH enhancement of excitatory synaptic transmission was gradual, requiring 60-70 min to reach maximum, and occurred without any change in paired-pulse facilitation, suggesting a possible postsynaptic site of action. In CA1 pyramidal neurons, GH enhancement of EPSPs was correlated with significant hyperpolarization and decreased input resistance. GH enhancement of EPSPs required Janus kinase 2 (JAK2), phosphatidylinositol-3 (PI3) kinase, mitogen-activated protein (MAP) kinase kinase (MEK), and synthesis of new proteins. Although PI3 kinase and MEK were required for initiation of GH effects on excitatory synaptic transmission, they were not required for maintained enhancement of EPSPs. GH treatment and tetanus-induced long-term potentiation were mutually occluding, suggesting a common mechanism or mechanisms in both forms of synaptic enhancement. Our results demonstrate that GH has powerful short-term effects on hippocampal function, and extend the timescale for potential roles of GH in regulating hippocampal function and hippocampal-dependent behaviors.
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PMID:Growth hormone enhances excitatory synaptic transmission in area CA1 of rat hippocampus. 1648 59

Neuronal cell death caused by pathophysiological over-activation of glutamate receptors and the subsequent CaII overloading, has been implicated in neurodegeneration after stroke, cerebral trauma and epileptic seizures. Recent findings suggest that certain progesterone metabolites (neurosteroids) such as allopregnanolone and dehydroepiandrosterone can protect neuronal cells from such insults. In the present study, murine P19 cells were induced to differentiate into postmitotic neurons expressing specific neuronal markers, including GABA(A) and NMDA receptors. Activation of NMDA receptors in P19-N neurons resulted in excitotoxic cell death, which involved suppression of the phosphorylation of the survival kinase PKB/Akt. Allopregnanolone and DHEA induced a rapid and prolonged phosphorylation of the Akt kinase and they were able to reverse the NMDA-induced suppression of the PI3-K/Akt pathway. The specificity of the neuroprotective effects of these neurosteroids was confirmed by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin, as well as by the GABA(A) receptor antagonist, bicuculline. The neurotoxic effect of NMDA on P19-N neurons was directly correlated with increased CaII entry, since the addition of EGTA or BAPTA-AM, significantly suppressed the NMDA-induced decrease of phospho-Akt and subsequent neuronal death. These results suggest that neurosteroids are able to act as survival factors on P19-N neurons, promoting the activation of the PI3-K/Akt pathway through a calcium-entry dependent mechanism.
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PMID:Induction of Akt by endogenous neurosteroids and calcium sequestration in P19 derived neurons. 1852

FYN belongs to the protein kinase family that phosphorylates NMDA receptor subunits, participating in the regulation of ion transmission and BDNF/TrkB signal transduction pathway. Lithium inhibits glutamatergic transmission via NMDA receptors, exerting neuroprotective effect against excitotoxicity. The aim of this study was to find possible association of three polymorphisms of FYN gene with prophylactic lithium response in the group of bipolar patients. We analyzed 101 bipolar patients treated with lithium carbonate for 5-27 years (mean 15 years). Twenty-four patients were identified as excellent lithium responders (ER), 51 patients as partial responders (PRs), and 26 patients were non-responders. Genotypes of the three analyzed polymorphisms were established by PCR-RFLP. Statistical analysis was done with Statistica. No significant differences in genotype distribution and allele frequencies were observed between T/G and A/G FYN polymorphisms and lithium response. We observed a trend toward association of TT genotype and T allele of T/C polymorphism with worse lithium response. The results of the study demonstrated only marginal association between FYN polymorphisms and prophylactic lithium response in bipolar patients. The results are discussed in light of our previous studies on FYN gene in bipolar illness and BDNF gene in lithium response.
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PMID:The association study of three FYN polymorphisms with prophylactic lithium response in bipolar patients. 1933 Jul 93

NMDA receptor subunit composition varies throughout the brain, providing molecular diversity in NMDA receptor function. The NR2 subunits (NR2A-D) in large part dictate the distinct functional properties of NMDA receptors and differentially regulate receptor trafficking. Although the NR2C subunit is highly enriched in cerebellar granule cells and plays a unique role in cerebellar function, little is known about NR2C-specific regulation of NMDA receptors. Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. Both growth factor stimulation and NMDA receptor activity lead to a robust increase in both phosphorylation of NR2C on S1096 and surface expression of cerebellar NMDA receptors. Finally, we find that NR2C expression, unlike NR2A and NR2B, supports neuronal survival. Thus, our data provide a direct mechanistic link between growth factor stimulation and regulation of cerebellar NMDA receptors.
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PMID:Growth factor-dependent trafficking of cerebellar NMDA receptors via protein kinase B/Akt phosphorylation of NR2C. 1947 50

Alzheimer's disease (AD) is a late-life cognitive disorder associated, among other things, to the presence of extracellular aggregates of fibrillar amyloid beta protein (Abeta). However, there is growing evidence that early stages of AD may be due to neuronal network dysfunction produced by the actions of soluble forms of Abeta. Therefore, the development of new therapeutic strategies to treat AD, at least during its first stages, may be focused on preventing or reversing, the deleterious effects that soluble Abeta exerts on neuronal circuit function. In order to do so, it is necessary to elucidate the pathophysiological processes involved in Abeta-induced neuronal network dysfunction and the molecular processes underlying such dysfunction. Over the last decades, there has been extensive research about the molecular mechanisms involved in the effects of Abeta as well as possible neuroprotective strategies against such effects. Here we are going to review some of the intracellular pathways triggered by Abeta, which involve membrane receptors such as nicotinic-R, NMDA-R, integrins, TNF-R1, RAGE, FPRL and p75NTR and their intracellular mediators such as GSK3, PKC, PI3K, Akt, FAK, MAPK family, Src family and cdk5. Several of these pathways may constitute therapeutic targets for the treatment of the Abeta-induced neuronal network dysfunction which is, at least in part, the basis for cognitive dysfunction in AD.
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PMID:Pharmacology of the intracellular pathways activated by amyloid beta protein. 1951 98


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