Dual pharmacological properties of a cyclic AMP-sensitive potassium channel.
Bovine adrenal zona fasciculata cells express a novel K+ current (IAC) that sets the resting potential while it couples adrenocorticotropin and angiotensin II receptors to membrane depolarization and cortisol secretion. IAC is distinctive among K+ channels both in its activation by ATP and its inhibition by cyclic AMP. Whole-cell and single-channel patch-clamp recording was used to establish a pharmacological profile of IAC K+ channels. IAC was blocked by antagonists of cyclic nucleotide-gated channels, including the diphenylbutylpiperidine (DPBP) antipsychotic pimozide and l-cis-diltiazem. Other DPBPs, including penfluridol and fluspirilene, also potently inhibited this channel. The inhibition of IAC by DPBPs was selective because 200-fold higher concentrations of penfluridol were required to inhibit voltage-gated IA K+ channels in adrenal zona fasciculata cells. Standard K+ channel antagonists blocked IAC at concentrations 100- to 100,000-fold higher than the DPBPs. IAC channels were also inhibited by the sulfonylureas glyburide and tolbutamide but at concentrations higher than those that typically block ATP-sensitive inward rectifier K+ channels. Overall, the relative order of potency and associated IC50 values for IAC antagonists were as follows: penfluridol (0.187 microM) > fluspirilene (0.232 microM) > pimozide (0.354 microM) >> l-cis-diltiazem (24.9 microM) approximately quinidine (24.1 microM) > bupivacaine (113.2 microM) > tolbutamide (784.4 microM) > BaCl2 (1027 microM) > 4-aminopyridine (2750 microM) > tetraethylammonium (24,270 microM). IAC channels are unique in combining the pharmacological properties of K+-selective channels with those of cyclic nucleotide-gated cation channels. The potent block of IAC channels identifies DPBPs as a new class of K+ channel antagonists and suggests additional targets for these neuroleptics in the central nervous system.
Gomora
J C
JC
Department of Pharmacology, The Ohio State University, College of Medicine, Columbus, Ohio, USA.
Enyeart
J J
JJ
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism*; D054815:Cyclic Nucleotide-Gated Cation Channels; D004110:Diltiazem / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010395:Penfluridol / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects*; D015383:Zona Fasciculata / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D014150:Antipsychotic Agents; D002121:Calcium Channel Blockers; D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D010395:Penfluridol; D000242:Cyclic AMP; D004110:Diltiazem