Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified a 70-kDa cytosolic protein (GTBP70) in rat adipocytes that binds to glutathione S-transferase fusion proteins corresponding to the cytoplasmic domains of the facilitative glucose transporter isoforms Glut1, Glut2, and Glut4. GTBP70 did not bind to irrelevant fusion proteins, indicating that the binding is specific to the glucose transporter. GTBP70 binding to the glucose transporter showed little isoform specificity but was significantly subdomain-specific; it bound to the C-terminal domain and the central loop, but not to the N-terminal domain of Glut4. The GTBP70 binding to Glut4 was not affected by the presence of 2 mM EDTA, 2.4 mM Ca2+, or 150 mM K+. The binding was inhibited by ATP in a dose-dependent manner, with 50% inhibition at 10 mM ATP. This inhibition was specific to ATP, as ADP and AMP-PCP (adenosine 5'-(beta, gamma-methylenetriphosphate)) were without effect. GTBP70 did not react with antibodies against phosphotyrosine, phosphothreonine, or phosphoserine, suggesting that it is not a phosphoprotein. The binding of GTBP70 to Glut4 was not affected by the pretreatment of adipocytes with insulin. When these experiments were repeated using rat hepatocyte cytosols, no ATP-sensitive 70-kDa protein binding to the glucose transporter fusion proteins was evident, suggesting that either GTBP70 expression or its function is cell-specific. These findings strongly suggest the possibility that GTBP70 may play a key role in glucose transporter regulation in insulin target cells such as adipocytes.
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PMID:ATP-sensitive binding of a 70-kDa cytosolic protein to the glucose transporter in rat adipocytes. 771 80

The largely empirical dopamine theory has limited value in clarifying the pathogenesis of schizophrenia, due to its inability to explain consistent imaging findings, such as cortical grey matter loss, reduced frontal and thalamic activity, and, reduced D1 receptor load. Furthermore, the most effective drug for treating positive and negative symptoms - clozapine - has minimal dopaminergic activity. We present an alternative hypothesis centring on presumed deficits in membrane bound glucose transporter proteins GLUT 1 and GLUT 3, either in absolute numbers or functional capacity. In situations of high demand, intracellular hypoglycaemia in neurones and astrocytes will produce acute symptoms of misperceptions, misinterpretations, anxiety and irritability - the usual features of prodromal and first onset schizophrenia. Furthermore, reduced glucose uptake will disrupt production of glutamate--functionally similar to the schizophrenia-like syndrome produced by PCP, a glutamate antagonist. In the longer term, reduced neuronal growth and poor synaptic contacts will produce chronic cognitive difficulties and perpetuate acute symptoms. A backlog effect due to reduced brain uptake of glucose would produce systemic hyperglycaemia observed in drug nai ve subjects. Rat studies have shown that clozapine and similar compounds block GLUT proteins in the brain and peripherally, more so than selective dopamine blockers. By blocking GLUT proteins, clozapine would break malfunctioning circuits, resulting in the disappearance of cognitive and perceptual symptoms. Unfortunately, these drugs would also raise systemic glucose levels, increasing the risk of diabetes, as observed in longer term studies of clozapine in particular. We summarise potentially useful research strategies, including studying the genotype of GLUT proteins with respect to schizophrenia phenotypes, activation studies involving fMRI using deoxyglucose as a substrate, and investigating clinical features of schizophrenic patients prior to and following treatment for co-existing diabetes.
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PMID:Impaired neuronal glucose uptake in pathogenesis of schizophrenia - can GLUT 1 and GLUT 3 deficits explain imaging, post-mortem and pharmacological findings? 1612 30