Discrepin Explained

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

Etymology and source

Discrepin is named after its source: a Venezuelan scorpion called Tityus discrepans.^[1] Its systematic number is α-KTx15.6.^[2]

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% amino acid homology 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 blocks voltage-gated Shal-type (Kv4.x) K⁺ channels in cerebellar granular cells.^{[1] [2]} These A-type K⁺ channels regulate firing frequency, spike initiation and the waveform of action potentials.^[2] Discrepin has 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 channels.^[2] The residues of discrepin that are important for blocking these channels have not yet been clarified. However, it is clear that the N-terminal plays a role in the binding affinity.^[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]} The kinetics of the channel are not affected by discrepin and the blockage is independent of the holding potential.^[2]

Toxicity

The half-effective dose (IC50) is 190 ± 30 nM.^[1]

Notes and References

1. D'Suze G, Batista CV, Frau A . 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 . Archives of Biochemistry and Biophysics . 430 . 2 . 256–63 . October 2004 . 15369825 . 10.1016/j.abb.2004.07.010. etal.
2. Prochnicka-Chalufour A, Corzo G, Satake H . Solution structure of discrepin, a new K+-channel blocking peptide from the alpha-KTx15 subfamily . Biochemistry . 45 . 6 . 1795–804 . February 2006 . 16460026 . 10.1021/bi0519248. etal.
3. Romeo S, Corzo G, Vasile A, Satake H, Prestipino G, Possani LD . 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 . Biochimica et Biophysica Acta (BBA) - General Subjects . 1780 . 4 . 750–5 . April 2008 . 18280256 . 10.1016/j.bbagen.2008.01.012.
4. Birnbaum SG, Varga AW, Yuan LL, Anderson AE, Sweatt JD, Schrader LA . Structure and function of Kv4-family transient potassium channels . Physiological Reviews . 84 . 3 . 803–33 . July 2004 . 15269337 . 10.1152/physrev.00039.2003.