1Homologues of dendrotoxin (Dtx) were isolated from the crude venom of Green and Black Mamba snakes and examined for K+ channel blocking activity in neonatal rat dorsal root ganglion cells (DRGs) by whole-cell patch clamp recording. 2 Outward potassium current activated by depolarization was composed of two major components: a slowly inactivating current (SIC, tdecay ; 50 ms, 200 ms and 2 s), and a non-inactivating current (NIC, tdecay> 2 min). Tail current analysis revealed two time constants of deactivation of total outward current, 3-12 ms and 50-150 ms (at -80 mV) which corresponded to SIC and NIC, respectively.3 All the homologues (a-, P-, 'y-and 6-Dtx and toxins I and K) blocked outward current activated by depolarization in a dose-dependent manner. The most potent in blocking total outward current was 6-Dtx (ECm of 0.5 ± 0.2 nM), although there were no statistically significant differences in potency between any of the homologues. 4 Qualitative differences in the nature of the block were noted between homologues. In particular, the block by 6-Dtx was time-dependent, whereas that by a-Dtx was not. 5 a-Dtx was a much better blocker of SIC (EC50 = 1.0 ± 0.4 nM) than was 6-Dtx (EC50 = 17.6 ± 5.8 nM). Furthermore, 6-Dtx was selective for NIC (EC5 ± 0.24 ± 0.03 nM) over SIC and reduced the slow component of tail currents (NIC), preferentially. On the other hand, a-Dtx did not significantly distinguish between SIC and NIC although tail current analysis showed that a-Dtx preferentially reduced the fast component of tail currents (SIC). 6 The results confirm, using direct electrophysiological methods, that homologues of dendrotoxins from Mamba snake venom block K+ channels in rat sensory neurones. Furthermore, a-Dtx and 6-Dtx distinguish between sub-types of K+ channels in these cells and may thus be useful pharmacological tools in other neuronal K+ channel studies.