Glucokinase Is the Likely Mediator of Glucosensing in Both Glucose-Excited and Glucose-Inhibited Central Neurons

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 7; pp. 2056 - 2065
• Main Authors: DUNN-MEYNELL, Ambrose A, ROUTH, Vanessa H, LING KANG, GASPERS, Larry, LEVIN, Barry E
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.07.2002
• Subjects: Animals; Biochemistry and metabolism; Biological and medical sciences; Biological transport; Brain - drug effects; Brain - enzymology; Brain - physiology; Brain research; Carotid Artery, Internal; Central nervous system; Diabetes; Diabetes research; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - drug effects; Genes, fos - drug effects; Glucokinase - genetics; Glucokinase - metabolism; Glucose; Glucose - administration & dosage; Glucose - pharmacology; Glucose metabolism; In Situ Hybridization; Infusions, Intra-Arterial; Insulin; Neurons; Neurons - drug effects; Neurons - enzymology; Neurons - physiology; Neuropeptides; Obesity; Obesity - metabolism; Physiological aspects; Physiological transport; Physiology; Rats; Rats, Sprague-Dawley; Transcription, Genetic - drug effects; Vertebrates: nervous system and sense organs; Weight Gain; United States; Rat; Enzyme; Transferases; Rodentia; Central nervous system; Glucose; Hypothalamus; Gene expression; Vertebrata; Mammalia; Neuron; Glucokinase; Brain (vertebrata)
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.7.2056

Glucokinase Is the Likely Mediator of Glucosensing in Both Glucose-Excited and Glucose-Inhibited Central Neurons Ambrose A. Dunn-Meynell 1 2 , Vanessa H. Routh 3 , Ling Kang 2 , Larry Gaspers 3 and Barry E. Levin 1 2 1 Department of Veterans Affairs Medical Center, East Orange, New Jersey 2 Department of Neurosciences, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 3 Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 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 γ-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. Footnotes Address correspondence and reprint requests to Barry E. Levin, MD, Neurology Service (127C), VA Medical Center, 385 Tremont Ave., East Orange, NJ 07018-1095. E-mail: levin{at}umdnj.edu . Received for publication 14 March 2002 and accepted in revised form 18 April 2002. ARC, arcuate nucleus; [Ca 2+ ] i , intracellular Ca 2+ ; DIO, diet-induced obesity; DR, diet resistance; GE, glucose-excited; GFAP, glial fibrillary acidic protein; GI, glucose-inhibited; GK, glucokinase; HBSS, Hanks’ balanced salt solution; IC 50 , half-maximal inhibitory concentration; K ATP channel, ATP-sensitive K + channel; NG, nonglucosensing; NPY, neuropeptide Y; NTS, nucleus tractus solitarius; POMC, pro-opiomelanocortin; VMN, ventromedial hypothalamic nucleus. DIABETES