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Vol. 290, Issue 1, 266-275, July 1999
Department of Pharmacology (J.C.G., J.J.E.) and The Neuroscience
Program (J.J.E.), The Ohio State University, College of Medicine,
Columbus, Ohio
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 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).
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.
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