TREMORGENIC INDOLE ALKALOIDS POTENTLY INHIBIT SMOOTH-MUSCLE HIGH-CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNELS

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.