Modulation of the excitability of cholinergic basal forebrain neurones by KATp channels

The expression of ATP-sensitive K+(K-ATP) channels by magnocellular cholinergic basal forebrain (BF) neurones was investigated in thin brain slice and dissociated cell culture preparations using a combination of whole-cell, perforated-patch and single-channel recording techniques. Greater than 95% of BF neurones expressed functional K-ATP channels whose activation resulted in membrane hyperpolarization and a profound fall in excitability. The whole-cell K-ATP conductance was 14.0 +/- 1.5 nS and had a reversal potential of -91.4 +/- 0.9 mV that shifted by 59.6 mV with a tenfold increase in [K+](o). I-KATP was inhibited reversibly by tolbutamide (IC50 of 34.1 mum) and irreversibly by glibenclamide (0.3-3 nM) and had a low affinity for [ATP] (i) (67% reduction with 6 mM [MgATP] (i)). Using perforated-patch recording, a small proportion of the conductance was found to be tonically active. This was weakly potentiated by diazoXide (0.1 mm extracellular glucose) but insensitive to pinacidil (less than or equal to 500 pm). Single-channel K-ATP currents recorded in symmetrical 140 mm K+-containing solutions exhibited weak inward rectification with a mean conductance of 66.2 +/- 1.9 pS. Channel activitywas inhibited byMgATP (>50 mum) and activated by MgADP (200 pm). The K+ channels opener diazoxide (200-500 mum) increased channel opening probability (NPO) by 486 120% whereas pinacidil (500 mum) had no effect. In conclusion, the characteristics of the K-ATP channels expressed by BF neurones are very similar to channels composed of SUR1 and Kir6.2 subunits. In the native cell, their affinity for ATP is close to the resting [ATP] (i), potentially allowing them to be modulated by physiologically relevant changes in [ATP] (i). The effect of these channels on the level of ascending cholinergic excitation of the cortex and hippocampus is discussed.