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Inhibition of human large conductance calcium-activated potassium channels by a fungal toxin

J.E. Dalziel1, S.C. Finch2 and J. Dunlop1, 1AgResearch Limited, Grasslands Research Centre, Private Bag 11008, Palmerston North, New Zealand and 2Ruakura Research Centre, Private Bag 3123, Hamilton, New Zealand.

The aim of this research was to investigate possible receptor/ion channel sites of action of a fungal toxin (designated compound A) that produces ataxia, tremors, and hypersensitivity to external stimuli when injected into mice. Compound A is distinct among neurotoxins in that it has a long duration of action, producing tremors that can last for up to three days rather than only a few hours. It also inhibits electrically stimulated smooth muscle contraction, increases neurotransmitter release, and elevates blood pressure. These effects suggested the disruption of large conductance calcium-activated potassium (BK) channels, as they have important regulatory roles in smooth muscle contraction and in control of neurotransmitter release (Gribkoff et al., 2001). We investigated this possibility using hSlo (α subunit) BK channels expressed in human embryonic kidney cells and patch-clamping. We discovered that compound A potently inhibits BK channel-activation at nanomolar concentrations in inside-out membrane patches. BK channel currents activated by depolarising voltage pulses in the presence of 10 μM free calcium were inhibited by compound A in a concentration-dependent manner. 100 nM compound A completely inhibited outward potassium currents in less than one minute. The concentration that produced half maximal inhibition was approximately 3 nM, indicating a high apparent affinity for BK channels. This is the first time a molecular site of action has been determined for a compound of this structural class and identifies a novel BK channel blocker.

Gribkoff V.K., Starrett J.E., Jr. & Dworetzky S.I. (2001) Neuroscientist, 7:166-77.