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PMID:12086933

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Citation

Dunn-Meynell, AA, Routh, VH, Kang, L, Gaspers, L and Levin, BE (2002) Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. Diabetes 51:2056-65

Abstract

Specialized neurons utilize glucose as a signaling molecule to alter their firing rate. Glucose-excited (GE) neurons increase and glucose-inhibited (GI) neurons reduce activity as ambient glucose levels rise. Glucose-induced changes in the ATP-to-ADP ratio in GE neurons modulate the activity of the ATP-sensitive K(+) channel, which determines the rate of cell firing. The GI glucosensing mechanism is unknown. We postulated that glucokinase (GK), a high-Michaelis constant (K(m)) hexokinase expressed in brain areas containing populations of GE and GI neurons, is the controlling step in glucosensing. Double-label in situ hybridization demonstrated neuron-specific GK mRNA expression in locus ceruleus norepinephrine and in hypothalamic neuropeptide Y, pro-opiomelanocortin, and gamma-aminobutyric acid neurons, but it did not demonstrate this expression in orexin neurons. GK mRNA was also found in the area postrema/nucleus tractus solitarius region by RT-PCR. Intracarotid glucose infusions stimulated c-fos expression in the same areas that expressed GK. At 2.5 mmol/l glucose, fura-2 Ca(2+) imaging of dissociated ventromedial hypothalamic nucleus neurons demonstrated GE neurons whose intracellular Ca(2+) oscillations were inhibited and GI neurons whose Ca(2+) oscillations were stimulated by four selective GK inhibitors. Finally, GK expression was increased in rats with impaired central glucosensing (posthypoglycemia and diet-induced obesity) but was unaffected by a 48-h fast. These data suggest a critical role for GK as a regulator of glucosensing in both GE and GI neurons in the brain.

Links

PubMed

Keywords

Animals; Brain/drug effects; Brain/enzymology; Brain/physiology; Carotid Artery, Internal; Gene Expression Regulation, Enzymologic/drug effects; Genes, fos/drug effects; Glucokinase/genetics; Glucokinase/metabolism; Glucose/administration & dosage; Glucose/pharmacology; In Situ Hybridization; Infusions, Intra-Arterial; Neurons/drug effects; Neurons/enzymology; Neurons/physiology; Obesity/metabolism; Rats; Rats, Sprague-Dawley; Transcription, Genetic/drug effects; Weight Gain

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:HXK4

involved_in

GO:0009749: response to glucose

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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