Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.1 (hexokinase)
 5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ceramide is a lipid second-messenger generated in response to stimuli associated with neurodegeneration that induces apoptosis, a mechanism underlying neuronal death in Parkinson's disease. We tested the hypothesis that insulin-like growth factor-1 (IGF-1) could mediate a metabolic response in CAD cells, a dopaminergic cell line of mesencephalic origin that differentiate into a neuronal-like phenotype upon serum removal, extend processes resembling neurites, synthesize abundant dopamine and noradrenaline and express the catecholaminergic biosynthetic enzymes tyrosine hydroxylase and dopamine beta-hydroxylase, and that this process was phosphatidylinositol 3-kinase (PI 3-K)-Akt-dependent and could be inhibited by C(2)-ceramide. The metabolic response was evaluated as real-time changes in extracellular acidification rate (ECAR) using microphysiometry. The IGF-1-induced ECAR response was associated with increased glycolysis, determined by increased NAD(P)H reduction, elevated hexokinase activity and Akt phosphorylation. C(2)-ceramide inhibited all these changes in a dose-dependent manner, and was specific, as it was not induced by the inactive C(2)-ceramide analogue C(2)-dihydroceramide. Inhibition of the upstream kinase, PI 3-K, also inhibited Akt phosphorylation and the metabolic response to IGF-1, similar to C(2)-ceramide. Decreased mitochondrial membrane potential occurred after loss of Akt phosphorylation. These results show that IGF-1 can rapidly modulate neuronal metabolism through PI 3-K-Akt and that early metabolic inhibition induced by C(2)-ceramide involves blockade of the PI 3-K-Akt pathway, and may compromise the first step of glycolysis. This may represent a new early event in the C(2)-ceramide-induced cell death pathway that could coordinate subsequent changes in mitochondria and commitment of neurons to apoptosis.
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PMID:Insulin-like growth factor-1-dependent maintenance of neuronal metabolism through the phosphatidylinositol 3-kinase-Akt pathway is inhibited by C2-ceramide in CAD cells. 1756 16

Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional Ser/Thr kinase that plays important roles in necrosis and apoptosis of cardiomyocytes. A major mechanism of cell necrosis is the opening of the mitochondrial permeability transition pore (mPTP), which consists of multiple protein subunits, including adenine nucleotide translocase (ANT). The threshold for mPTP opening is elevated by phosphorylation of GSK-3beta at Ser9, which reduces activity of this kinase. How inactivation of GSK-3beta suppresses mPTP opening has not been fully understood, but evidence to date suggests that preservation of hexokinase-II in the mPTP complex, inhibition of cyclophilin-D-ANT binding, inhibition of p53 and inhibition of ANT into the mitochondria are contributory. GSK-3beta phosphorylation is a step to which multiple protective signaling pathways converge, and thus GSK-3beta phosphorylation is crucial in cardioprotection of a variety of interventions against ischemia/reperfusion injury. Apoptosis of cardiomyocytes by pressure overload or ischemia/reperfusion is also suppressed by inactivation of GSK-3beta, in which reduced phosphorylation of p53, heat shock factor-1 and myeloid cell leukemia sequence-1 and inhibition of Bax translocation might be involved. Considering predominant roles of GSK-3beta in cardiomyocyte death, manipulation of this protein kinase is a promising strategy for myocardial protection in coronary artery disease and heart failure.
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PMID:GSK-3beta, a therapeutic target for cardiomyocyte protection. 1950 20

The etiology of Parkinson's disease remains unknown. Mutations in PINK1 have provided an understanding of the molecular mechanisms of this pathology. PINK1 and Parkin are important in the dismissal of dysfunctional mitochondria. However, the role of PINK1 in the control of neuronal survival pathways is not clear. To determine the role of PINK1 in the control of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediated by insulin-like grow factor type 1 (IGF-1), we use a model of mesencephalic neurons (CAD cells), which were transfected with lentiviral PINK1 shRNA or control shRNA constructs. Silencing of PINK1 was determined by RT-PCR and immunoblotting; cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays; proteins of the PI3K/Akt signaling pathway were tested by immunoblotting and IGF-1 receptor, and mitochondria were examined using fluorescence microscopy. PINK1 shRNA-transfected cells showed a reduction in cell survival compared to control shRNA cells. Exposure to IGF-1 induced a rapid and high increase in the phosphorylation level of IGF-1 receptor in control shRNA-transfected cells; however, silencing of PINK1 decreases phosphorylation level of IGF-1 receptor and downstream target proteins such as Akt, GSK3-beta, IRS-1, and hexokinase. Our results further suggest that PINK1 may be regulating the PI3K/Akt neuronal survival pathway through tyrosine kinase receptors such as IGF-1 receptor.
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PMID:Silencing of PINK1 inhibits insulin-like growth factor-1-mediated receptor activation and neuronal survival. 2553 21