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)

We tested the hypothesis that a subset of enteric neurons is glucoresponsive and expresses ATP-sensitive K(+) (K(ATP)) channels. The immunoreactivities of the inwardly rectifying K(+) channel 6.2 (Kir6.2) and the sulfonylurea receptor (SUR), now renamed SUR1, subunits of pancreatic beta-cell K(ATP) channels, were detected on cholinergic neurons in the guinea pig ileum, many of which were identified as sensory by their costorage of substance P and/or calbindin. Glucoresponsive neurons were distinguished in the myenteric plexus because of the hyperpolarization and decrease in membrane input resistance that were observed in response to removal of extracellular glucose. The effects of no-glucose were reversed on the reintroduction of glucose or by the K(ATP) channel inhibitor tolbutamide. No reversal of the hyperpolarization was observed when D- mannoheptulose, a hexokinase inhibitor, was present on the reintroduction of glucose. Application of the K(ATP) channel opener diazoxide or the ob gene product leptin mimicked the effect of glucose removal in a reversible manner; moreover, hyperpolarizations evoked by either agent were inhibited by tolbutamide. Glucoresponsive neurons displayed leptin receptor immunoreactivity, which was widespread in both enteric plexuses. Superfusion of diazoxide inhibited fast synaptic activity in myenteric neurons, via activation of presynaptic K(ATP) channels. Diazoxide also produced a decrease in colonic motility. These experiments demonstrate for the first time the presence of glucoresponsive neurons in the gut. We propose that the glucose-induced excitation of these neurons be mediated by inhibition of K(ATP) channels. The results support the idea that enteric K(ATP) channels play a role in glucose-evoked reflexes.
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PMID:Identification and characterization of glucoresponsive neurons in the enteric nervous system. 1057 28

The transcription factor Foxa2 is implicated in blood glucose homeostasis. Conditional expression of Foxa2 or its dominant-negative mutant DN-Foxa2 in INS-1 cells reveals that Foxa2 regulates the expression of genes important for glucose sensing in pancreatic beta-cells. Overexpression of Foxa2 results in blunted glucose-stimulated insulin secretion, whereas induction of DN-Foxa2 causes a left shift of glucose-induced insulin release. The mRNA levels of GLUT2 and glucokinase are drastically decreased after induction of Foxa2. In contrast, loss of Foxa2 function leads to up-regulation of hexokinase (HK) I and II and glucokinase (HK-IV) mRNA expression. The glucokinase and the low K(m) hexokinase activities as well as glycolysis are increased proportionally. In addition, induction of DN-Foxa2 also reduces the expression of beta-cell K(ATP) channel subunits Sur1 and Kir6.2 by 70%. Furthermore, in contrast to previous reports, induction of Foxa2 causes pronounced decreases in the HNF4alpha and HNF1alpha mRNA levels. Foxa2 fails to regulate the expression of Pdx1 transcripts. The expression of insulin and islet amyloid polypeptide is markedly suppressed after induction of Foxa2, while the glucagon mRNA levels are significantly increased. Conversely, Foxa2 is required for glucagon expression in these INS-1-derived cells. These results suggest that Foxa2 is a vital transcription factor evolved to control the expression of genes essential for maintaining beta-cell glucose sensing and glucose homeostasis.
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PMID:Foxa2 (HNF3beta ) controls multiple genes implicated in metabolism-secretion coupling of glucose-induced insulin release. 1187 61