Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K+ channels

Abstract

Intracellular recordings were made from neurones located in the ventromedial hypothalamic nucleus (VMHN) of slices from rat hypothalamus. These neurones were hyperpolarized on removal of extracellular glucose, resulting in an inhibition of firing, actions which were reversed on the re-introduction of glucose. No reversal of the inhibition of firing was observed when 10 mM mannoheptulose, an inhibitor of glucose metabolism, was present in addition to glucose. Increasing the mannoheptulose concentration to 20 mM resulted in further hyperpolarization. Cell-attached recordings from isolated neurones revealed that an increase in extracellular glucose inhibited a K+ channel and increased action current activity. ATP induced closure of this K+ channel when applied to inside-out membrane patches. Closure was also induced by Mg-free ATP or the non-hydrolysable ATP-analogue, adenylylimidodiphosphate indicating no requirement for ATP metabolism. We suggest that the closure of ATP-sensitive potassium channels underlies increased hypothalamic firing following an increase in extracellular glucose.

The effect of modafinil on counter-regulatory and cognitive responses to hypoglycaemia

“…Hypoglycaemia is associated with an increase in c-fos activity in this region of the brain [37]. A growing body of evidence suggests that the glucosesensing neurones of the hypothalamus and elsewhere in the brain respond to changes in plasma glucose using mechanisms similar to those used by the pancreatic beta cell [4,5,6,7,8]. In the latter, a decrease in glucose concentration suppresses insulin secretion.…”

Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

“…Glucose-excited (GE) neurons increase, whereas glucose-inhibited (GI) neurons decrease their firing rate as ambient glucose levels rise (2)(3)(4). Although these neurons can respond directly or indirectly to either the complete absence of glucose or to levels as high as 20 mmol/l (2,(5)(6)(7)(8)(9), it is likely that their primary range is 0.5-3.5 mmol/l glucose under physiological conditions (4,10 -12). As in the pancreatic ␤-cell (13), the ATP-sensitive K ϩ (K ATP ) channel is an important component of glucosensing in GE neurons (3,5,14).…”

“…Although these neurons can respond directly or indirectly to either the complete absence of glucose or to levels as high as 20 mmol/l (2,(5)(6)(7)(8)(9), it is likely that their primary range is 0.5-3.5 mmol/l glucose under physiological conditions (4,10 -12). As in the pancreatic ␤-cell (13), the ATP-sensitive K ϩ (K ATP ) channel is an important component of glucosensing in GE neurons (3,5,14). The K ATP channel is an octameric protein consisting of a pore-forming, inwardly rectifying K ϩ channel (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR-1 and -2) subunit (15)(16)(17)(18).…”

“…GK-mediated ATP production raises the ATP-to-ADP ratio and inactivates the K ATP channel. The increased ATP-to-ADP ratio leads to membrane depolarization, Ca 2ϩ influx, and increased insulin release in the ␤-cell (24) and increased firing rate in glucosensing neurons (3)(4)(5)8,9,24). Most neurons express hexokinase-I (HK-I), which is unlikely to regulate the rate of glycolysis because it is both saturated at physiological brain glucose levels and inhibited by its product, glucose-6-phosphate (25,26).…”

“…Most neurons express hexokinase-I (HK-I), which is unlikely to regulate the rate of glycolysis because it is both saturated at physiological brain glucose levels and inhibited by its product, glucose-6-phosphate (25,26). For this reason, GE neurons might use GK as a regulatory step in glucosensing (5,8,10,27). Inhibition of GK activity decreases intracellular Ca 2ϩ ([Ca 2ϩ ] i ) oscillations in dissociated hypothalamic GE neurons and decreases firing of GE neurons in hypothalamic slices (5,8,10,27).…”