Tremorgenic indole alkaloids produce neurological disorders (e.g., sta
ggers syndromes) in ruminants. The mode of action of these fungal myco
toxins is not understood but may be related to their known effects on
neurotransmitter release. To determine whether these effects could be
due to inhibition of K+ channels, the interaction of various indole di
terpenes with high-conductance Ca2+-activated K+ (maxi-K) channels was
examined. Paspalitrem A, paspalitrem C, aflatrem, penitrem A, and pas
palinine inhibit binding of [I-125]charybdotoxin (ChTX) to maxi-K chan
nels in bovine aortic smooth muscle sarcolemmal membranes. In contrast
, three structurally related compounds, paxilline, verruculogen, and p
aspalicine, enhanced toxin binding. As predicted from the binding stud
ies, covalent incorporation of [I-125]ChTX into the 31-kDa subunit of
the maxi-K channel was blocked by compounds that inhibit [I-125]ChTX b
inding and enhanced by compounds that stimulate [I-125]ChTX binding. M
odulation of [I-125]ChTX binding was due to allosteric mechanisms. Des
pite their different effects on binding of [I-125]ChTX to maxi-K chann
els, all compounds potently inhibited maxi-K channels in electrophysio
logical experiments. Other types of voltage-dependent or Ca2+-activate
d K+ channels examined were not affected. Chemical modifications of pa
xilline indicate a defined structure-activity relationship for channel
inhibition. Paspalicine, a deshydroxy analog of paspalinine lacking t
remorgenic activity, also potently blocked maxi-K channels. Taken toge
ther, these data suggest that indole diterpenes are the most potent no
npeptidyl inhibitors of maxi-K channels identified to date. Some of th
eir pharmacological properties could be explained by inhibition of max
i-K channels, although tremorgenicity may be unrelated to channel bloc
k.