Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons.
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.
Dunn-Meynell
Ambrose A
AA
Neurology Service, Department of Veterans Affairs Medical Center, 385 Tremont Avenue, East Orange, NJ 07018-1095, USA.
Routh
Vanessa H
VH
Kang
Ling
L
Gaspers
Larry
L
Levin
Barry E
BE
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D002343:Carotid Artery, Internal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D017403:In Situ Hybridization; D007261:Infusions, Intra-Arterial; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D009765:Obesity / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects; D015430:Weight Gain
D005941:Glucokinase; D005947:Glucose