Dendrotoxins: Structure-Activity Relationships and Effects on Potassium Ion Channels

Abstract

Dendrotoxins are small proteins isolated from mamba (Dendroaspis) snakes. The original dendrotoxin was found in venom of the Eastern green mamba, Dendroaspis angusticeps, and related proteins were subsequently found in other mamba venoms. The dendrotoxins contain 57-60 amino acid residues cross-linked by three disulphide bridges, and they are homologous to Kunitz-type serine protease inhibitors, such as aprotinin (BPTI). The dendrotoxins have little or no anti-protease activity, but they block particular subtypes of voltage-dependent potassium channels of the Kv1 subfamily in neurones. Alpha-dendrotoxin from green mamba Dendroaspis angusticeps and toxin I from the black mamba Dendroaspis polylepis block cloned Kv1.1, Kv1.2 and Kv1.6 channels in the low nanomolar range; toxin K, also from the black mamba Dendroaspis polylepis, preferentially blocks Kv1.1 channels and is active at picomolar concentrations. Structural modifications and mutations to dendrotoxins have helped to define the molecular recognition properties of different types of K+ channels, although more work is needed to characterise the chemical features of the toxins that underlie their selectivity and potency at particular subtypes of channels. Dendrotoxins have been useful markers of subtypes of K+ channels in vivo, and dendrotoxins have become widely used as probes for studying the function of K+ channels in physiology and pathophysiology. With some pathological conditions being associated with voltage-gated K+ channels, analogues of dendrotoxins might have therapeutic potential.

Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels

“…The effects of DTx-K, a related polypeptide that selectively blocks Kv1.1-containing channels (Harvey and Robertson, 2004) on the cold threshold, were nearly identical to those observed with ␣-DTx. On average, 1 M DTx-K shifted the threshold by 3.5 Ϯ 0.8°C (n ϭ 19) (supplemental Table 1, available at www.jneurosci.org as supplemental material).…”

“…The blocking actions of DTx-K and tityustoxin-K␣ indicate that Kv1.1 and Kv1.2 are part of the channel complex forming I KD (Wang et al, 1999;Harvey and Robertson, 2004) and excludes homomeric Kv1.2 channels, which are insensitive to DTx-K. Intriguingly, Kv1.1 knock-out mice show prominent cold-induced discharges in myelinated motor nerves (Zhou et al, 1998).…”

“…We tested whether ␣-DTx (Stühmer et al, 1989;Harvey and Robertson, 2004), a specific blocker of some Shaker potassium channel subunits (Kv1.1, Kv1.2, and Kv1.6) affected I KD and thermal threshold in identified CS neurons. A 1 M concentration of ␣-DTx blocked a slow outward current activated at subthreshold potentials (Fig.…”

Postnatal development of A-type and Kv1- and Kv2-mediated potassium channel currents in neocortical pyramidal neurons

“…We previously determined dose-response relationships for the blockers, and we chose doses that were specific for the relevant subunits (Guan et al 2006(Guan et al , 2007b. To study putative Kv1-mediated current (Guan et al 2006), we applied 100 nM ␣-dendrotoxin (DTX, blocks current through channels containing Kv1.1, Kv1.2, or Kv1.6 subunits; Harvey and Robertson 2004) and 10 -30 nM margatoxin (MTX, blocks Kv1.3-containing channels; Garcia-Calvo et al 1993). The putative Kv1-mediated current was defined as the difference between currents recorded in control solution and currents in the presence of DTX plus MTX.…”

Potassium Channel Modulation by a Toxin Domain in Matrix Metalloprotease 23

“…It has been suggested that toxins evolved from endogenous genes that function in normal cellular pathways (3,4). Indeed, venomous creatures possess toxins with homology to several proteins, including acetylcholinesterases (5), phospholipases (6,7), nerve growth factor (8), endothelins (9), Lynx-1 (10,11), Kunitz-type serine protease inhibitors (12), and the ion channel regulatory (ICR) 5 domains of cysteinerich secretory proteins (CRISPs) (3,13,14). Mammalian proteins containing toxin-like domains (TxDs) that block K ϩ channels have not been characterized previously.…”