Scorpion toxin block of the early K+ current (IKf) in rat dorsal root ganglion neurones.

1. The ability of three structurally homologous scorpion toxins to block voltage-dependent K+ currents in rat dorsal root ganglion neurones was examined using the patch-clamp technique. 2. Neurones with a diameter > 35 microns had two identifiable components of macroscopic K+ current. The outward current during depolarizations had both inactivating and non-inactivating components, and the tail currents had both a fast component (IKf) with a time constant of about 2.5 ms and a slow component (IKs) with a time constant of about 10 ms. 3. The functional properties of IKf and IKs differed in several ways: (i) IKf activated over a more negative voltage range than IKs; (ii) IKf partially inactivated during a depolarization to +70 mV, whereas IKs did not inactivate during a 1 s depolarization to +70 mV; (iii) IKf activated more rapidly than IKs; and (iv) alpha-dendrotoxin selectively blocked IKf. 4. Tityustoxin-K alpha (TsTX-K alpha) selectively blocked IKf, with little or no effect on IKs. The block was concentration dependent, with 50% of the current inhibited at a toxin concentration of about 38 nM. 5. TsTX-K alpha block of IKf was completely reversible, but the washout rate was slow. The time constant of recovery from TsTX-K alpha block was about 11 min. 6. Charybdotoxin (CTX) also selectively blocked IKf in a reversible manner, but was about 10 times less potent than TsTX-K alpha. The CTX washout rate was over 10 times faster than that of TsTX-K alpha; the time constant of recovery was 0.8 min. 7. Pandinotoxin-K alpha (PiTX-K alpha) also selectively blocked IKf; the IC50 for block of IKf was about 8.1 nM. In contrast to the other two toxins, however, PiTX-K alpha was poorly reversible. 8. The block of IKf produced by CTX was voltage dependent. In the voltage range from -10 to +70 mV, the fraction of blocked IKf fell from 91 to 37%. In contrast, both TsTX-K alpha and PiTX-K alpha blocked IKf in a voltage-independent manner. 9. The backbone structure and many of the amino acid side-chains on the presumed docking surfaces of the toxins are identical or conservatively replaced in all three toxins. Thus, some small differences in a few side-chains that influence electrostatic, hydrophobic/hydrophilic and/or steric interactions probably account for the marked differences in affinities and dissociation rates.