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)

Chronic stimulation of norepinephrine (NE) neuromodulation by angiotensin II (Ang II) involves activation of the Ras-Raf-MAP kinase signal transduction pathway in Wistar Kyoto (WKY) rat brain neurons. This pathway is only partially responsible for this heightened action of Ang II in the spontaneously hypertensive rat (SHR) brain neurons. In this study, we demonstrate that the MAP kinase-independent signaling pathway in the SHR neuron involves activation of PI3-kinase and protein kinase B (PKB/Akt). Ang II stimulated PI3-kinase activity in both WKY and SHR brain neurons and was accompanied by its translocation from the cytoplasmic to the nuclear compartment. Although the magnitude of stimulation by Ang II was comparable, the stimulation was more persistent in the SHR neuron compared with the WKY rat neuron. Inhibition of PI3-kinase had no significant effect in the WKY rat neuron. However, it caused a 40-50% attenuation of the Ang II-induced increase in norepinephrine transporter (NET) and tyrosine hydroxylase (TH) mRNAs and [3H]-NE uptake in the SHR neuron. In contrast, inhibition of MAP kinase completely attenuated Ang II stimulation of NET and TH mRNA levels in the WKY rat neuron, whereas it caused only a 45% decrease in the SHR neuron. However, an additive attenuation was observed when both kinases of the SHR neurons were inhibited. Ang II also stimulated PKB/Akt activity in both WKY and SHR neurons. This stimulation was 30% higher and lasted longer in the SHR neuron compared with the WKY rat neuron. In conclusion, these observations demonstrate an exclusive involvement of PI3-kinase-PKB-dependent signaling pathway in a heightened NE neuromodulatory action of Ang II in the SHR neuron. Thus, this study offers an excellent potential for the development of new therapies for the treatment of centrally mediated hypertension.
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PMID:Role of phosphatidylinositol 3-kinase in angiotensin II regulation of norepinephrine neuromodulation in brain neurons of the spontaneously hypertensive rat. 1008 56

Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.
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PMID:Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration. 1113 81

Human alpha-synuclein (halpha-SYN) is implicated in the Parkinson's disease phenotype (PDP) based on a variety of studies in man, animal models, and in vitro studies. The normal function of halpha-SYN and the mechanism by which it contributes to the PDP remains unclear. We created transgenic mice expressing either wild-type (hwalpha-SYN) or a doubly mutated (hm2alpha-SYN) form of halpha-SYN under control of the 9-kb rat tyrosine hydroxylase promoter. These mice expressed halpha-SYN in cell bodies, axons, and terminals of the nigrostriatal system. The expression of halpha-SYN in nigrostriatal terminals produced effects in both constructs resulting in increased density of the dopamine transporter and enhanced toxicity to the neurotoxin MPTP. Expression of hm2alpha-SYN reduced locomotor responses to repeated doses of amphetamine and blocked the development of sensitization. Adult hwalpha-SYN-5 transgenic mice had unremarkable dopaminergic axons and terminals, normal age-related measures on two motor coordination screens, and normal age-related measures of dopamine (DA) and its metabolites. Adult hm2alpha-SYN-39 transgenic mice had abnormal axons and terminals, age-related impairments in motor coordination, and age-related reductions in DA and its metabolites. Expression of hm2alpha-SYN adversely affects the integrity of dopaminergic terminals and leads to age-related declines in motor coordination and dopaminergic markers.
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PMID:Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. 1200 58

The goal of this study was to determine the immunohistochemical characteristics of peripheral adrenergic OBR-immunoreactive (OBR-IR) neurons innervating adipose tissue in a pig. The retrograde tracer, Fast Blue (FB), was injected into either the subcutaneous, perirenal, or mesentery fat tissue depots of three male and three female pigs each with approximately 50 kg body weight. Sections containing FB(+) neurons were stained for OBR, tyrosine hydroxylase (TH) or neuropeptide Y (NPY) using a double labeling immunofluorescence method. OBR, TH, and NPY immunoreactivities were present in the thoracic (T) and lumbar (L) ganglia of the sympathetic chain, as well as in the coeliac superior mesenteric ganglion (CSMG), inferior mesenteric ganglion (IMG), intermesenteric ganglia (adrenal-ADG, aorticorenal-ARG, and ovarian-OG or testicular-TG ganglion). These results indicate that, in addition to neuroendocrine functions, leptin may affect peripheral tissues by acting on receptors located in sympathetic ganglion neurons.
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PMID:Leptin receptors, NPY, and tyrosine hydroxylase in autonomic neurons supplying fat depots in a pig. 1205 78

The extracellular regulated kinase (ERK) pathway was studied to determine its role in neuronal plasticity related to the development of nicotine dependence. Levels and phosphorylation state of ERK, cAMP response element binding protein (CREB) and proline-rich/Ca2+-activated tyrosine kinase (PYK2), and levels of tyrosine hydroxylase (TH), were determined using western blotting. C57Bl/6J mice received acute or chronic nicotine (200 microg/mL) in their drinking water or were withdrawn from nicotine for 24 h following chronic exposure. CREB phosphorylation was reduced in the nucleus accumbens following chronic nicotine, consistent with previous reports that decreased accumbens CREB activity increases drug reinforcement. In contrast, CREB phosphorylation was increased in the prefrontal cortex following chronic nicotine exposure and in the ventral tegmental area during nicotine withdrawal. In addition, total and phosphorylated ERK decreased in the amygdala following chronic nicotine exposure, but ERK phosphorylation increased in the prefrontal cortex. TH levels increased in both the amygdala and prefrontal cortex, supporting the hypothesis that increased catecholaminergic tone contributes to nicotine reinforcement. Overall, these results support a role for ERK and CREB activity in neural plasticity associated with nicotine dependence.
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PMID:In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. 1261 43

Enhanced blood pressure variability contributes to left ventricular hypertrophy and end-organ damage, even in the absence of hypertension. We hypothesized that the greater number of high-blood pressure episodes associated with enhanced blood pressure variability causes cardiac hypertrophy and dysfunction by activation of mechanosensitive and autocrine pathways. Normotensive mice were subjected to sinoaortic baroreceptor denervation (SAD) or sham surgery. Twelve weeks later, blood pressure variability was doubled in SAD compared with sham-operated mice. Blood pressure did not differ. Cardiac hypertrophy was reflected in greater heart/body weight ratios, larger myocyte cross-sectional areas, and greater left ventricular collagen deposition. Furthermore, left ventricular atrial and brain natriuretic peptide mRNA expression was greater in SAD than in sham-operated mice. SAD had higher left ventricular end-diastolic pressures and lower myocardial contractility indexes, indicating cardiac dysfunction. Cardiac protein content of phosphorylated p125 focal adhesion kinase (p125 FAK) and phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) was greater in SAD than in sham-operated mice, indicating activation of mechanosensitive pathways of cardiac hypertrophy. Furthermore, enhanced cardiac renin and transforming growth factor-beta1 (TGFbeta1) protein content indicates activation of autocrine pathways of cardiac hypertrophy. Adrenal tyrosine hydroxylase protein content and the number of renin-positive glomeruli were not different, suggesting that sympathetic activation and the systemic renin-angiotensin system did not contribute to cardiac hypertrophy. In conclusion, more frequent blood pressure rises in subjects with high blood pressure variability activate mechanosensitive and autocrine pathways leading to cardiac hypertrophy and dysfunction even in the absence of hypertension.
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PMID:Mechanisms of blood pressure variability-induced cardiac hypertrophy and dysfunction in mice with impaired baroreflex. 1556 77

The poor differentiation and survival of dopaminergic neurones are practical constraints in their therapeutic applications. Here we explored the role of neuronally activated Ras in ventral mesencephalon-derived neurospheres generated from synRas mouse embryos. The expression of Val12 Ha-Ras transgene and enhanced Ras activity was evident after differentiation of the neurospheres with a corresponding activating phosphorylation of mitogen-activated protein kinase. Phosphorylation of Akt/PKB, the target kinase of phosphoinositide 3-kinase, along with phosphorylation of Bad and CREB were enhanced in synRas-derived differentiated neurosphere cultures. Furthermore, increased Nurr1 expression was associated with elevated numbers of dopaminergic neurones in synRas-derived cultures compared with the wild-type. Correspondingly, tyrosine hydroxylase promoter assays revealed enhanced transcriptional activation of the promoter in synRas-derived cultures. synRas-derived dopaminergic neurones were greatly resistant to degeneration induced by various noxious stimuli. Consistently, the transgenic expression of activated Ras attenuated the adverse 6-hydroxydopamine effects on dopaminergic neurones. Dopaminergic neurones derived from both wild-type and synRas cultures expressed voltage-gated potassium and sodium currents, fired action potentials and exhibited electrical network activity. Thus, expression of the transgene promotes survival and enhances differentiation towards a dopaminergic cell fate without altering their basic electrical properties. Our results suggest that intracellular cell therapy mimicking trophic signalling may offer potential benefit in models of human disease associated with dopamine neurone dysfunction.
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PMID:Enhancement of dopaminergic properties and protection mediated by neuronal activation of Ras in mouse ventral mesencephalic neurones. 1743 85

alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease (PD). Previous studies have shown that alpha-synuclein is involved in the regulation of dopamine (DA) metabolism, possibly by down-regulating the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in DA biosynthesis. In this study, we constructed alpha-synuclein stably silenced MN9D/alpha-SYN(-) cells by vector mediated RNA interference and examined its effects on DA metabolism. We found that there were no significant differences in TH protein and mRNA levels between MN9D, MN9D/alpha-SYN(-) and MN9D/CON cells, suggesting that silencing alpha-synuclein expression does not affect TH gene expression. However, significant increases in phosphorylated TH, cytosolic 3, 4-dihydroxyphenylalanine (L-DOPA) and DA levels were observed in MN9D/alpha-SYN(-) cells. Our data show that TH activity and DA biosynthesis were enhanced by down-regulation of alpha-synuclein, suggesting that alpha-synuclein may act as a negative regulator of cytosolic DA. With respect to PD pathology, a loss of functional alpha-synuclein may result in increased DA levels in neurons that may lead to cell injury or even death.
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PMID:Silencing alpha-synuclein gene expression enhances tyrosine hydroxylase activity in MN9D cells. 1835 27

Significant attention has been drawn to the potential role of defective PI3-kinase-Akt (PKB) signalling in Parkinson's disease (PD) neurodegeneration and to the possibility that activation of Akt may provide neuroprotection in PD. However, little knowledge exists on the integrity of the Akt system in PD. Results of the present study show diminished levels of both total and active phospho(Ser473)-Akt in the brain in PD. This was evident by western blot analysis of midbrain fractions from PD compared to non-PD control brain, but more specifically by immunofluorescence microscopy of the substantia nigra pars compacta (SNpc). Here, double immunofluorescence microscopy found Akt and phospho(Ser473)-Akt to be expressed at high levels in tyrosine hydroxylase (TH) immunopositive dopaminergic neurons in control human brain. Selective loss of these neurons was accompanied by a marked decrease of Akt and phospho(Ser473)-Akt expression in the PD brain, however Akt and active phospho(Ser473)-Akt are still evident in degenerating dopaminergic neurons in the disease. This suggests that it may be possible to target neuronal Akt in advanced PD. Converse to the marked loss of neuronal Akt in PD, increased Akt and phospho(Ser473)-Akt levels were observed in small non-TH positive cells in PD SNpc, whose increased number and small nuclear size indicate they are glia. These findings implicate defective Akt as a putative signalling pathway linked to loss of dopaminergic neurons in PD.
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PMID:Akt signal transduction dysfunction in Parkinson's disease. 1980 Mar 94

In the present work we report the generation of a new line of alpha-synuclein (alpha-SYN) transgenic mice in which the human wild-type alpha-SYN cDNA is expressed under the control of a tyrosine hydroxylase (TH) promoter. We provide evidence that the ectopic protein is found in TH expressing neurons of both central and peripheral nervous systems. The transgene is expressed very early in development coinciding with the activity of the TH promoter and in the adult brain the human protein distributes normally to the nerve endings and cell bodies of dopaminergic nigral neurons without any evidence of abnormal aggregation. Our results indicate that expression of human wild-type alpha-SYN does not affect normal development or maintenance of TH immunoreactive nigral neurons, striatal dopamine content, or locomotor activity. Systemic administration of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a loss of TH immunoreactive nigral neurons and terminals and of dopamine levels to the same degree in both transgenic and non-transgenic adult mice. Intoxication also results in a similar loss of cardiac noradrenaline in both genotypes. Surprisingly, cultured transgenic ventral mesencephalic fetal dopaminergic neurons exhibit complete resistance to cell death induced by 1-methyl-4-phenylpyridinium ion (MPP(+)) intoxication, without changes in dopamine transporter (DAT) surface levels. Interestingly, this protection is not observed in other populations of catecholaminergic neurons such as peripheral sympathetic neurons, despite their high sensitivity to MPP(+)in vitro.
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PMID:Prosurvival effect of human wild-type alpha-synuclein on MPTP-induced toxicity to central but not peripheral catecholaminergic neurons isolated from transgenic mice. 2015 26


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