Discrepin

Discrepin (α-KTx15.6) is a peptide from the venom of the Venezuelan scorpion Tityus discrepans.^[1] It acts as a neurotoxin through irreversibly blocking the currents of the voltage-dependent K⁺-channel.

Etymology and source

Discrepin is named after its source; a Venezuelan scorpion called Tityus discrepans.^[1] Its systematic number is α-KTx15.6.^[2] α-KTx stands for the subfamily of K⁺-channel toxins classified by their primary structures and functions. The number 15 indicates that this is the fifteenth subfamily reported to be specific for this subtype of K⁺-channels. The number 6 means that discrepin is the sixth toxin identified in the subfamily α-KTx15.

Chemistry

The subfamily α-KTx15 consists of 6 toxins. The first five toxins of this subfamily are very much alike, but discrepin only shares 50% of amino acids with other members of this subfamily.^[1] Discrepin contains 38 amino acid residues. It has a polyglutamic acid at its N-terminal region.^[3] Discrepin has the α and β folds that are characteristic of scorpion toxins.^[2] It consists of one α-helix and three β-sheet helix strands. The α-helix is formed from amino acid Ser11 until Arg21. The three antiparallel β-sheets are formed from amino acid Ile2 until Lys7, Ala27 until Cys29 and Arg33 until Cys36.

Target

Discrepin has been shown to block A-type K⁺ currents in cerebellar granular cells, belonging to the voltage-gated Shal-type Kv4.x K⁺channels.^[1,2] Regulated by these channels are the firing frequency, spike initiation and the waveform of action potentials.^[2] Discrepin is yet only been tested in cerebellar cells, however Kv4.x family channels are in general highly expressed in the brain, heart and smooth muscles.^[4] Competition experiments showed that discrepin inhibits the binding of scorpion toxin BmTx3 to its receptor site, where other K⁺ channel blockers (Kv1-, Kv3.4-, Kv4.2/4.3 family blockers) were unable to compete with this toxin. These results support the hypothesis that discrepin can bind to a very specific and unique type of Kv4.x receptor channel.^[2] The residues of discrepin that are important for blocking these channels have not been clarified yet. However it is clear that the N-terminal plays a role on the affinity of binding.^[3] The stoichiometry of toxin binding to the potassium channel is 1:1.^[3]

Mode of action

Discrepin specifically blocks the I_A currents (fast transient, low voltage activated currents) of voltage-dependent K+ channels. Inhibition of these K⁺ currents occurs in an irreversible manner, i.e. washing out of the toxin gives no recovery of the currents.^[1,2] To produce a blockade, an open state of the channel is not necessary. Moreover the affinity of discrepin is not influenced by the open or closed state of the channel, an open state does not increase the affinity.^[1] The kinetics of the channel are not affected by discrepin and the blockage is independent of the test potentials.^[2]

Toxicity

The conductance of the K⁺ channels is affected in a dose-dependent manner, at high concentration the steady state inhibition was reached rapidly. The half-effective dose (IC50), given by the Michaelis-Menten equation, is a toxin concentration of 190 ± 30 nM.^[1]

References

1. Gina D’Suze (October 2004), "Discrepin, a new peptide of the sub-family alpha-ktx15, isolated from the scorpion Tityus discrepans irreversibly blocks K⁺ -channels (IA currents) of cerebellum granular cells", Arch Biochem Biophys., 430(2): 256–63

2. Ada Prochnicka-Chalufour et al. (February 2006), "Solution structure of discrepin, a new K⁺-channel blocking peptide from the alpha-KTx15 subfamily", Biochemistry, 45(6): 1795–804

3. Stefania Romeo et al. (April 2008), "A positive charge at the N-terminal segment of Discrepin increases the blocking effect of K⁺ channels responsible for the IA currents in cerebellum granular cells", Biochim Biophys Acta, 1780(4): 750–5

4. SG Birnbaum et al. (July 2004), "Structure and function of Kv4-family transient potassium channels", Physiol Rev., 84(3): 803–33