Modulation of the excitability of cholinergic basal forebrain neurones by K ATP 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 (IC 50 of 34.1 μ m ) and irreversibly by glibenclamide (0.3–3 n m ) and had a low affinity for [ATP] i (67% reduction with 6 m m [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 m m extracellular glucose) but insensitive to pinacidil (≤500 μ m ). Single‐channel K ATP currents recorded in symmetrical 140 m m K + ‐containing solutions exhibited weak inward rectification with a mean conductance of 66.2 ± 1.9 pS. Channel activity was inhibited by MgATP (>50 μ m ) and activated by MgADP (200 μ m ). The K + channels opener diazoxide (200–500 μ m ) increased channel opening probability ( NP o ) by 486 ± 120% whereas pinacidil (500 μ m ) 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.