Potassium channel dysfunction in hypothalamic glucose-receptive neurones of obese Zucker rats

1. We have shown, using intracellular and cell-attached recordings, that glucose-receptive (GR) neurones of obese Zucker rats exhibit abnormal electrophysiological responses to changes in extracellular glucose concentration, whereas GR neurones of lean Zucker and control rats respond normally. 2. In inside-out recordings from obese rat GR neurones it was shown that the 150 pS ATP-sensitive K+ (KATP) and the 160 pS calcium-activated K+ (KCa) channels were absent, whereas both were present in GR neurones of lean Zucker and control rats. 3. The potassium channel most frequently observed in inside-out patches from obese GR neurones was characterized by a conductance of 213 pS, was activated by raising internal calcium and inhibited by application of internal ATP. This channel (which we have termed Kfa) was not observed in lean or control rat GR neurones. 4. Tolbutamide (100 microM) was found to induce no effect or to elicit a small depolarization of obese rat GR neurones in the absence of glucose, in contrast to its clear excitatory actions on control or lean Zucker GR neurones. 5. Intracellular, cell-attached and inside-out recordings from obese rat non-GR neurones showed that there was no alteration in their membrane properties or firing characteristics or in the characteristics of the large-conductance calcium-activated K+ channel (KCa) present in these neurones as compared with lean and control rats. 6. It is concluded that the Kfa channel is specific to GR neurones of obese Zucker rats and that the presence of this channel coupled with the absence of KATP and KCa channels results in the abnormal glucose-sensing response of these neurones.