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 (IC(50) of 34.1 microM) 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 (< or =500 microM). 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 activity was inhibited by MgATP (>50 microM) and activated by MgADP (200 microM). The K(+) channels opener diazoxide (200-500 microM) increased channel opening probability (NP(o)) by 486 +/- 120% whereas pinacidil (500 microM) 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.
Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. t.allen@ucl.ac.uk
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D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D000255:Adenosine Triphosphate