Glucose-induced intracellular ion changes in sugar-sensitive hypothalamic neurons.

Abstract

In the lateral hypothalamic area (LHA) of rat brain, approximately 30% of cells showed sensitivity to small changes in local concentrations of glucose. These "glucose-sensitive" neurons demonstrated four types of behavior, three of which probably represent segments of a continuous spectrum of recruitment in response to ever more severe changes in blood sugar. Type I cells showed maximum activity </=5.6 mM blood glucose but became completely silent at hyperglycemia of 10-12 mM (normoglycemia 7.6 +/- 0.3 mM; mean +/- SD). Type II and III neurons exhibited a wider range of response. Type IV cells (5-7% of glucose-sensitive neurons) paralleled the behavior of sugar-sensitive cells in ventromedial hypothalamic nucleus (VMH). In VMH, approximately 40% of cells responded to changes in blood glucose over a range of concentrations from 3.6 to 17 mM, by increasing their firing rate as sugar level rose and vice versa. Ionic shifts during increases in blood (brain) glucose levels were similar in LHA types I-III but fastest in I and slowest in III. [Na+]i fell by 5-9 mM, [K+]i rose by 6-8 mM, and plasma membrane hyperpolarized by 5 mV. [Ca2+]i declined by 15-20 nM in line with membrane hyperpolarization. In VMH and type IV LHA cells, [K+]i fell 3-8 mM and plasma membrane depolarized -3 to -5 mV as blood/brain glucose concentration increased from 7.6/2.4 to 17.6/4.2 mM, whereas [Ca2+]i increased from 125 to 180 nM as a consequence of falling membrane potential. During falls in blood/brain sugar concentration the effects in both VMH and LHA cells were reversed. The findings are consistent with the ionic shifts in types I-III LHA cells being dependent on alterations in Na/K-ATPase activity, whereas those in VMH and type IV LHA cells could be caused by modulation of ATP-dependent K+ channels. A possible mechanism for linking the effects of small changes in glucose to ATP generation, which could bring about the above phenomena, is the interposition of a "glucokinase-type" enzyme in a role similar to that which it has in glucose-sensing pancreatic beta-cells.