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Department of Pharmacology, University College London, Gower Street, London WC1E 6BT
The expression of ATP-sensitive K+ (KATP) 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 KATP channels whose activation resulted in membrane hyperpolarization and a profound fall in excitability. The whole-cell KATP 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. IKATP was inhibited reversibly by tolbutamide (IC50 of 34.1 µM) 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 (
500 µM). Single-channel KATP currents recorded in symmetrical 140 mM K+-containing solutions exhibited weak inward rectification with a mean conductance of 66.2 ± 1.9 pS. Channel activity was inhibited by MgATP (>50 µM) and activated by MgADP (200 µM). The K+ channels opener diazoxide (200–500 µM) increased channel opening probability (NPo) by 486 ± 120% whereas pinacidil (500 µM) had no effect. In conclusion, the characteristics of the KATP 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.
(Received 26 September 2003;
accepted after revision 23 October 2003;
first published online 24 October 2003)
Corresponding author T. G. J. Allen: Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: t.allen{at}ucl.ac.uk
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