Dual Pharmacological Properties of a Cyclic AMP-Sensitive Potassium Channel1

Abstract

Bovine adrenal zona fasciculata cells express a novel K⁺current (I_AC) that sets the resting potential while it couples adrenocorticotropin and angiotensin II receptors to membrane depolarization and cortisol secretion. I_AC 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 I_AC K⁺ channels. I_AC was blocked by antagonists of cyclic nucleotide-gated channels, including the diphenylbutylpiperidine (DPBP) antipsychotic pimozide andl-cis-diltiazem. Other DPBPs, including penfluridol and fluspirilene, also potently inhibited this channel. The inhibition of I_AC by DPBPs was selective because 200-fold higher concentrations of penfluridol were required to inhibit voltage-gated I_A K⁺ channels in adrenal zona fasciculata cells. Standard K⁺ channel antagonists blocked I_AC at concentrations 100- to 100,000-fold higher than the DPBPs. I_AC 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 I_AC antagonists were as follows: penfluridol (0.187 μM) > fluspirilene (0.232 μM) > pimozide (0.354 μM) ≫l-cis-diltiazem (24.9 μM) ≈ quinidine (24.1 μM) > bupivacaine (113.2 μM) > tolbutamide (784.4 μM) > BaCl₂ (1027 μM) > 4-aminopyridine (2750 μM) > tetraethylammonium (24,270 μM). I_AC channels are unique in combining the pharmacological properties of K⁺-selective channels with those of cyclic nucleotide-gated cation channels. The potent block of I_ACchannels identifies DPBPs as a new class of K⁺ channel antagonists and suggests additional targets for these neuroleptics in the central nervous system.