Kurtoxin

The First Peptidic T-type Ca²⁺-Channel Blocker

Voltage-dependent Ca²⁺-channels are classified according to the nature of their a₁ subunits. High voltage-activated channels (HVA) are composed of a_1A-a_1F/a_1S, leading to L-, N-, P/Q- and R-type channels. Peptidic blockers specific for each channel are commercially available List of Ion Channel Blockers. Low voltage-activated channels (LVA) are encoded by a_1G-a_1I, which correspond to T-type channels. Although these channels are known to be blocked by Ni²⁺ ions, until recently there was no peptidic blocker for this particular channel.

Kurtoxin:
Lys-Ile-Asp-Gly-Tyr-Pro-Val-Asp-Tyr-Trp-Asn-Cys-Lys-Arg-Ile-Cys-Trp-Tyr-Asn-Asn- Lys-Tyr-Cys-Asn-Asp-Leu-Cys-Lys-Gly-Leu-Lys-Ala-Asp-Ser-Gly-Tyr-Cys-Trp-Gly-Trp- Thr-Leu-Ser-Cys-Tyr-Cys-Gln-Gly-Leu-Pro-Asp-Asn-Ala-Arg-Ile-Lys-Arg-Ser-Gly-Arg- Cys-Arg-Ala

However, in 1998, a new T-type channel blocker, kurtoxin, was isolated from the venom of the South African scorpion (Parabuthus transvaalicus). This compound is a 63 amino acid residue peptide with 4 intramolecular disulfide linkages[Nat. Neurosci., 1, 668 (1998) ]. Using the expressed a_1G channel, the binding of kurtoxin was found to involve 1:1 stoichiometry with a K_d value of 15 nM. Almost complete inhibition by kurtoxin was observed for the a_1G channel at 350 nM, whereas the a_1H channel was blocked approximately 85% at the same concentration. a_1A- a_1C and a_1E Channels were not affected at 350 nM, indicating the specific blocking activity of kurtoxin for the expressed T-type channels. Because of the sequence similarity with a-scorpion toxins, kurtoxin binds to voltage-gated Na⁺ channels and slows their inactivation. Later, it was clarified that this peptide interacts with both HVA and LVA channels in rat central and peripheral neurons: i) N- and L-type channel currents were partially inhibited by 250-500 nM peptide (Kd=456 nM and 72 nM, respectively), ii) P-type Ba²⁺ current in Purkinje neurons was facilitated by 500 nM peptide (K_d=14 nM), and iii) K_d for thalamic T-type channels was 49 nM[J. Neurosci., 22, 2023 (2002) ]. The reason for this discrepancy between two reports remains to be clarified, however. T-type channel blocking activity of kurtoxin is attractive because this peptide does interact with both expressed and native T-type channels.

Kurtoxin is a useful blocker for T-type channels, especially when used in combination with the various blockers for HVA channels for further research investigations.