Metabolic inhibition and low internal ATP activate K-ATP channels in rat dopaminergic substantia nigra neurones.
The patch-clamp technique was used to study whole-cell currents of acutely dissociated rat substantia nigra (SN) neurones. In perforated-patch current-clamp recordings, inhibition of mitochondrial metabolism by rotenone (5 microM) produced a hyperpolarisation and inhibited electrical activity. These effects were reversed by the sulphonylureas tolbutamide (0.5 mM) or glibenclamide (0.5 microM). Under voltage-clamp conditions, rotenone induced a time- and voltage-independent K+ current which was selectively blocked by sulphonylureas. The glibenclamide-sensitive current reversed at -81.7 +/- 2.7 mV (n = 5) and showed marked inward rectification. Intracellular dialysis with 0.3 mM adenosine 5'-triphosphate (ATP), but not 2 mM or 5 mM ATP, in standard whole-cell recordings also resulted in activation of a sulphonylurea-sensitive K+ current with similar properties (reversal potential, -81.9 +/- 2.5 mV, n = 5). The close similarity in the properties of the ATP-sensitive K+ current observed in whole-cell recordings and the K+ current activated by metabolic inhibition in perforated-patch recordings suggest that they both result from activation of the same type of ATP-sensitive K+ channel. Sulphonylureas had no effect on electrical activity or membrane currents in the absence of rotenone in perforated-patch recordings, or in cells dialysed with 5 mM ATP, indicating that in SN neurones these drugs are selective for the ATP-sensitive K+ current.
Röper
J
J
University Laboratory of Physiology, Oxford, UK.
Ashcroft
F M
FM
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002395:Catecholamines / Q000032:analysis*; D002469:Cell Separation; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012402:Rotenone / Q000494:pharmacology; D013378:Substantia Nigra / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000494:pharmacology
D002395:Catecholamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D012402:Rotenone; D000255:Adenosine Triphosphate; D011188:Potassium; D005905:Glyburide